CN1635891A

CN1635891A - Tetrahydroquinoline analogues as muscarinic agonists

Info

Publication number: CN1635891A
Application number: CNA028270495A
Authority: CN
Inventors: 尼尔斯·肖杰埃贝克; 克瑞斯蒂恩·鲁普·科克; 博·伦纳特·米卡埃尔·弗里贝里; 博-拉格纳·托尔夫
Original assignee: Acadia Pharmaceuticals Inc
Current assignee: Acadia Pharmaceuticals Inc
Priority date: 2001-12-28
Filing date: 2002-12-23
Publication date: 2005-07-06
Anticipated expiration: 2022-12-23
Also published as: IL162616A0; RU2004123203A; NO327522B1; EP1461318A2; NZ533566A; BR0215430A; DK1461318T3; EP1461318B1; IL162616A; US7576100B2; HK1074573A1; ATE304533T1; NO20043013L; AU2002359875B2; JP2005519060A; US7307075B2; US20060199813A1; JP4509565B2; US20060199810A1; CN100402032C

Abstract

The present invention relates to tetrahydroquinoline compounds as formulas I, as well as salts and isomers thereof wherein m is 0, 1 or 2; C3-C4 is CH2-CH or CH=C or C4 is CH and C3 is absent; L<1> and L<2> are biradicals independently selected from the group consisting of -C(R<6>)=C(R<7>), -C(R<6>)=N-, -N=C(R<6>)-, -S-, -NH- and -O-; wherein only one of L<1> and L<2> may be selected from the group consisting of -S-, NH - and O; Y is selected from the group consisting of O, S, and H2; X is a biradical as muscarinic receptor agonists; compositions comprising the same; methods of inhibiting an activity of a muscarinic receptor with said compounds; methods of treating a disease condition associated with a muscarinic receptor using said compounds; and methods for identifying a subject suitable for treatment using said compounds.

Description

Tetrahydroquinoline analogues as muscarinic agonist

Invention field

[0001] the present invention relates to influence cholinoceptor, especially influence the chemical compound of muscarinic receptor.The invention provides the chemical compound as cholinergic agonist, cholinoceptor comprises muscarinic receptor, especially the M of muscarinic receptor ₁And M ₄Hypotype.The present invention also provides and uses the chemical compound that is provided to regulate the method for the disease relevant with cholinoceptor, especially treat or alleviate the disease relevant with muscarinic receptor, as with M ₁And/or M ₄The disease that receptor subtype is relevant.

Background

[0002] muscarinic cholinergic receptor can mediate the reaction of the neurotransmitters acetylcholine in maincenter and the peripheral nervous system.Muscarinic receptor plays a part crucial, and it can mediate senior cognitive function in the central nervous system, and it can mediate heart, breathing, digestion and endocrine and external secretion reaction in the periphery parasympathetic nervous system.Five kinds of different muscarinic receptor hypotypes: M have been identified ₁-M ₅Muscarinic M ₁Receptor subtype is mainly expressed in cerebral cortex, and is considered to relevant with the control of senior cognitive function; M ₂Receptor is the main hypotype of finding in heart, and its control with heart rate is relevant; M ₃Receptor is wide expression in many peripheral tissues, and is considered to gastrointestinal and urethral stimulant and perspiration and salivates relevant; M ₄Receptor is present in the brain, and may be relevant with motion; M ₅Receptor is present in the brain, and its function is at present also uncertain.M ₁And M ₄With dopaminergic system special relatedness is arranged.

[0003] is accompanied by the minimizing of the acetyl choline content in the brain with cognitive impairment diseases associated such as Alzheimer disease (Alzheimer ' s disease).This is considered to the result owing to the cholinergic neuron degeneration of basal forebrain, and cholinergic neuron is subjected to the innervation in a plurality of zones of brain, comprises main cortex and the Hippocampus relevant with level process.

[0004] effort of raising levels of acetylcholine concentrates on and increases choline (acetylcholine synthesizes precursor) level and blockage of acetylcholine esterase (AChE) (enzyme of metabolism acetylcholine).Verified with the trial that strengthens the central cholinergic system function by choline or lecithin administration is unsuccessful.Have therapeutic efficiency though shown the AChE inhibitor, because the stimulation of periphery acetylcholine finds that it often has the cholinergic side effect, comprise abdominal colic, feel sick, vomit and diarrhoea.In about 1/3rd subject patients, can be observed these gastrointestinal side-effects.In addition, found some AChE inhibitor,, in about 30% patient, can be observed the obvious liver poisoning that the raising owing to liver transaminase causes as tetrahydroaminoacridine.The ill effect of AChE inhibitor has seriously limited their clinical practice.

[0005] dopamine hypothesis of schizophrenia shows that the dopamine neurotransmission of increase is the reason of this disease positive symptom, and has obtained the support of evidence, and promptly dopamine receptor-blocking agent can improve the evidence of this psychotic symptoms effectively.In addition, the medicine that improves dopamine neurotransmission in the brain can cause the people to produce and the similar situation of psychosis, and increases the weight of schizophrenic's psychotic symptoms.In zooscopy, increase the influence on can the generation behavior of the medicine of dopamine neurotransmission, suppress defective as many moving, climbings and prepulse.Known psychosis and dopamine-receptor antagonist can be blocked the influence in these behaviors.Unfortunately, dopamine-receptor antagonist also can cause side reaction outside the serious tractus pyramidalis in the patient, predicted as inducing of catalepsy in animal model, the outer side reaction influence of these tractus pyramidaliies comprise tremble, bradykinesia, the difficulty of sitting quietly and tardive dyskinesia.

[0006] partly because these observations has M ₁The reagent of receptor agonist activity has been found and has been used for the treatment of dementia.Yet existing reagent lacks specificity to the effect of different muscarinic receptor hypotypes.Also find known M ₁It is M for muscarinic agonist such as arecoline ₂And M ₃The weak agonist of receptor subtype, and do not having effect aspect the treatment cognitive impairment, this is attributed to the M of dose limitation to a great extent ₂And M ₃The side reaction that receptor mediated.

[0007] accounts for Nuo Meilin (Xanomeline) (Shannon etc., J.Pharmacol.Exp.Ther.1994,269,271; Shannon etc., Schizophrenia Res.2000,42,249) be a kind of M ₁/ M ₄Preferred muscarinic receptor agonist does not suppress the A9 dopaminergic cell although it can suppress A10, but very little or do not have with the affinity of dopamine receptor.Report thiadiazoles derivative PTAC (Shannon etc., European Journal of Pharmacology, 1998,356,109) has been arranged to muscarinic M ₂And M ₄Receptor has the agonist effect of part, to M ₁, M ₃And M ₅Receptor has antagonist action, shows functional dopamine antagonism simultaneously.

[0008] nearest, the verified muscarinic agonist that accounts for Nuo Meilin that comprises has the activity similar to known psychosis in animal model, but can not cause catalepsy (Bymaster etc., Eur.J.Pharmacol.1 998,356, and 109, Bymaster etc., Life Sci.1999,64,527, Shannon etc., J Pharmacol.Exp.Ther.1999,290,901, Shannon etc., Schizophrerzia Res.2000,42,249).In addition, account for Nuo Meilin and show and can alleviate the psychotic behavior symptom, as Alzheimer disease patient's illusion, suspicious, make a lot of noise and illusion (Bodick etc., Arch.Neurol.1997,54,465), however the side reaction that causes of treatment has seriously restricted the clinical practice of this chemical compound.

[0009] it is reported (Sauerberg etc., J.Med Chem.1998,41,4378) 1,2,5-thiadiazoles analog and maincenter muscarinic receptor have high-affinity and selectivity, although simultaneously dopamine receptor is lacked affinity, shows functional dopamine antagonism.

[0010] the application's researcher partly is devoted to design a kind of molecule, and this molecule can improve negative symptoms and cognitive impairment as the non compos mentis medicine of new treatment when alleviating the positive symptom relevant with schizophrenia.The purpose of the application's researcher is the D that proof has combination ₂The muscarinic M of antagonist activities ₁And/or M ₄Agonist has psychosis effect preferably, and does not produce independent use high dose D ₂The side effect that antagonist is relevant.The D of chemical compounds more of the present invention ₂The antagonist attribute helps to alleviate the positive symptom of disease.

[0011] based on M ₁And M ₄The distribution of receptor in cerebral cortex and Hippocampus (this zone is relevant with senior cognitive function), the M of these chemical compounds ₁And/or M ₄The agonist attribute can be alleviated cognitive blunt, and may improve the negative symptoms relevant with schizophrenia (Friedman, Biol.Psychiatry, 1999,45,1; Rowley, J.Med.Chem.2001,44,477; Felder, J Med Chem.2000,43,4333).This unique combination for the central nervous system's behavior in certain molecule is unprecedented, may cause producing a kind of psychosis of brand-new type, and this medical instrument has preferably clinical attributes and can not produce restrictive side effect.

[0012] US 3,324,137 and US 3,365,457 N-[indyl-rudimentary-alkanoyl is disclosed]-1,5-imino group cycloalkanes and not by imino group cycloalkanes that the present invention comprised.

[0013] EP 0 584 487 disclose not by the present invention comprised be connected with piperazine ring 4,5-dihydro-4-oxygen-pyrroles.

[0014] Mokrosz etc. (Pharmazie 52,1997,6, p423) discloses not by N-[3-(4-the aryl)-1-piperazinyl of indoline-2 (1H)-ketone, quinoline-2-(1H)-ketone and isoquinolin-1-(2H)-ketone that the present invention comprised] propyl group] derivant.

Summary of the invention

[0015] the invention provides noval chemical compound shown in the general formula I and salt thereof and isomer

R wherein ¹Be univalent perssad, it is selected from the C that selectively replaces _1-6-alkyl, the C that selectively replaces _2-6-alkylidene, the C that selectively replaces _2-6-thiazolinyl, the C that selectively replaces _2-6-alkynyl, the O-C that selectively replaces _1-6-alkyl, the O-C that selectively replaces _2-6-thiazolinyl, the O-C that selectively replaces _2-6-alkynyl, the S-C that selectively replaces _1-6-alkyl, the S-C that selectively replaces _2-6-thiazolinyl, the S-C that selectively replaces _2-6-alkynyl;

M is 0,1 or 2;

C ₃-C ₄Be CH ₂-CH or CH=C, perhaps C ₄Be CH and C ₃Do not exist;

R ²And R ³The C that be independently selected from hydrogen, selectively replaces _1-6Alkyl, the O-C that selectively replaces _1-6Alkyl, halogen, hydroxyl, or R ²And R ³Form ring system together;

R ⁴And R ⁵In each C that is independently selected from hydrogen, halogen, hydroxyl, selectively replaces _1-6-alkyl, the O-C that selectively replaces _1-6Alkyl, the aryl-C that selectively replaces _1-6Alkyl and the assorted alkyl of the aryl that selectively replaces;

L ¹And L ²Be divalent group, it is independently selected from-C (R ⁶)=C (R ⁷) ,-C (R ⁶)=N-,-N=C (R ⁶)-,-S-,-NH-and-O-; L wherein ¹And L ²In only have one and can be selected from-S-,-NH-and-O-;

Y is selected from O, S and H ₂

X is a divalent group, and it is selected from-C (R ⁶) (R ⁷)-C (R ⁶) (R ⁷)-,-C (R ⁶)=C (R ⁷)-,-O-C (R ⁶) (R ⁷)-, C (R ⁶) (R ⁷)-O-,-S-C (R ⁶) (R ⁷)-,-C (R ⁶) (R ⁷)-S-,-N (R ^N)-C (R ⁶) (R ⁷)-,-C (R ⁶) (R ⁷)-N (R ^N)-,-C (R ⁶) (R ⁷)-C (R ⁶) (R ⁷)-C (R ⁶) (R ⁷)-,-O-C (R ⁶) (R ⁷)-C (R ⁶) (R ⁷)-, S-C (R ⁶) (R ⁷)-C (R ⁶) (R ⁷)-, N (R ^N)-C (R ⁶) (R ⁷)-C (R ⁶) (R ⁷)-,-C (R ⁶) (R ⁷)-C (R ⁶) (R ⁷)-O ,-C (R ⁶) (R ⁷)-C (R ⁶) (R ⁷)-S ,-C (R ⁶) (R ⁷)-C (R ⁶) (R ⁷)-N (R ^N)-,-C (R ⁶) (R ⁷)-C (R ⁶)=C (R ⁷)-and-C (R ⁶)=C (R ⁷)-C (R ⁷) (R ⁷), R wherein ⁶And R ⁷Be independently selected from hydrogen, halogen, hydroxyl, nitro, cyano group, NR ^NR ^N, N (R ^N)-C (O) N (R ^N), the C that selectively replaces _1-6-alkyl, C _2-6-thiazolinyl, C _2-6-alkynyl, the O-C that selectively replaces _1-6The O-aryl of-alkyl, selectively replacement, the O-C that selectively replaces _2-6-thiazolinyl, the O-C that selectively replaces _2-6-alkynyl,

R wherein ^NThe C that is selected from hydrogen and selectively replaces _1-6-alkyl.

[0016] the present invention also provides compositions, and it contains

I) chemical compound of one or more general formula Is, and

Ii) at least a pharmaceutically acceptable excipient or carrier.

[0017] the present invention also provides the method for treatment mammal such as people's disease, and wherein the activity of cholinoceptor is regulated relevant with the useful reaction of physiology in the described mammiferous described disease.In one embodiment, method comprises the compound administration with the general formula I of effective dose.

[0018] thereby, the invention provides treatment or prevention or alleviate one or more and the method for mammal such as people's not normal relevant symptom, described not normal relevant with muscarinic receptor, for example with M ₁The muscarinic receptor hypotype is relevant.In one embodiment, method comprises chemical compound, its pharmaceutically acceptable salt, its stereoisomer of the general formula I of effective dose or contains the pharmaceutical composition administration of any above-mentioned substance.Available especially the inventive method treatment not normal for example comprises Alzheimer disease (Alzheimer ' s disease), Parkinson's disease (Parkinson ' s disease), schizophrenia, Huntington chorea (Huntington ' s chorea), family ataxia (Friederich ' sataxia), Ji Liedela tells auspicious syndrome (Gilles de la Tourette ' s Syndrome), Down's syndrome (Down Syndrome), Niemann-Pick disease (Pick disease), dull-witted, clinical melancholia, with age cognitive decline relatively, cognitive impairment, forgetful, confusion, lose memory, note disappearance, the blindness, depressed, pain, sleep disordered, psychosis, sudden infant death syndrome, intraocular pressure increases and glaucoma.

[0019] the present invention also provides a kind of treatment non compos mentis method, and wherein the useful reaction of physiology is because to M ₁Agonism, M ₁And M ₄Agonism, M ₁Agonism and D ₂Antagonism or M ₁And M ₄Agonism and D ₂The adjusting of antagonism.

[0020] the present invention's pharmaceutical composition of chemical compound, its pharmaceutically acceptable salt, its stereoisomer of general formula I also being provided or containing any above-mentioned substance is used for the treatment of purposes in disease relevant with cholinoceptor or its part or the not normal medicine in preparation.

[0021] the invention provides the method that preparation is used for the treatment of disease or not normal medicine thus, this disease or be selected from Alzheimer disease, Parkinson's disease, schizophrenia, Huntington chorea, family ataxia, Ji Liedela unusually and tell auspicious syndrome, Down's syndrome, Niemann-Pick disease, dementia, clinical melancholia, increase and glaucoma with age cognitive decline, cognitive impairment, forgetful, confusion relatively, memory loss, attention disappearance, the blindness, depression, pain, sleep disordered, psychosis, sudden infant death syndrome, intraocular pressure.

[0022] the present invention also provides the method that improves cholinergic receptor activity.In one embodiment, method comprises that the system that makes cholinoceptor or contain cholinoceptor contacts with the chemical compound of at least a general formula I of effective dose to improve the activity of cholinoceptor.

[0023] the invention provides test kit, the directions for use that it comprises one or more The compounds of this invention and is used to implement the inventive method.In one embodiment, directions for use is treatment or prevention or alleviates one or more and mammal such as people's not normal relevant symptom, and is described not normal relevant with muscarinic receptor, for example with M ₁The muscarinic receptor hypotype is relevant.In another embodiment, directions for use is to improve cholinergic receptor activity or activation cholinoceptor.

Invention description

[0024] for illustrative purposes, technical term will be used to limit fully to give a definition.

[0025] term " agonist " is defined as can strengthening the active chemical compound of this receptor when it contacts with receptor.

[0026] term " antagonist " is when being defined as bind receptor and the chemical compound of agonist or inverse agonist competition, thus suppress or blocking-up agonist or inverse agonist to the effect of receptor.Yet antagonist (" neutrality " antagonist is otherwise known as) is to the not effect of essential receptor active.

[0027] term " inverse agonist " is defined as reducing receptor basis active chemical compound (that is, by receptor-mediated signal).This chemical compound negativity antagonist that is otherwise known as.Inverse agonist is the part of receptor, and it makes receptor with respect to be in inactive state under the base state that takes place when lacking any part and exist.Thereby when antagonist suppressed agonist active, inverse agonist was the part that can change receptor conformation in the presence of the agonist lacking.The notion of inverse agonist is to be proposed in Nature 374:272 (1995) by people such as Bond.More specifically, Bond etc. proposes non-coordinate β ₂There is balance in-adrenoceptor between nonactive conformation and spontaneous activity conformation.But agonist is considered to the receptor in the stabilizing active conformation.Otherwise inverse agonist is considered to stablize nonactive receptor conformation.Thereby when antagonist shows when suppressing agonist active, inverse agonist also shows activity to the spontaneous nuclear transformation of activity conformation lacking in the presence of the agonist by suppressing non-coordinate receptor.

[0028] " M ₁-receptor " be defined as activity and M ₁The corresponding receptor of muscarinic receptor hypotype, it can be learned with the pharmacology by molecular cloning and characterize.

[0029] term " experimenter " refers to a kind of animal, mammal for example, and as the people, the object that it is treated, observes or tests.

[0030] term " optionally " is defined as the character of chemical compound, and the amount of this chemical compound is enough to influence the purpose reaction of specific receptor type, hypotype, kind or subspecies, to the activity of other receptor type then basically seldom or not influence.

[0031] EC of agonist ₅₀Be intended to refer in viewed for reaching the concentration of 50% maximum reaction required compound such as analyzed in vitro such as R-SAT.The EC of inverse agonist ₅₀Be intended to refer to that under not having the foundation level of chemical compound R-SAT reaction reaches the concentration of 50% required compound when suppressing.

[0032] reactive compound on the term pharmacology used herein " being total to administration " refers to the conveying of the chemical agent that two or more are independent, and no matter in external or body.Carry when altogether administration refers to independent medicament; Carry in the time of pharmaceutical mixture; And carry a kind of medicament to carry second kind or other medicament then.In all cases, the medicament combination with one another of administration works altogether.

[0033] in the context of the present invention, term " C _1-6-alkyl " be meant the saturated hydrocarbon chain of straight or branched, wherein the longest chain has 1 to 6 carbon atom, as methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, isobutyl group, sec-butyl, the tert-butyl group, amyl group, isopentyl, neopentyl and hexyl.

[0034] in the context of the present invention, term " C _2-8-thiazolinyl " looking like is meant the straight or branched alkyl that has 2 to 8 carbon atoms and contain one or more pairs of keys.C _2-8The illustrative example of-thiazolinyl comprises pi-allyl, high allyl, vinyl, crotyl, cyclobutenyl, pentenyl, hexenyl, heptenyl and octenyl.Contain C more than two keys _2-8The illustrative example of-thiazolinyl comprises butadienyl, pentadienyl, hexadienyl, heptadiene base, heptantriene base and sarohornene base and side chain form thereof.Unsaturated bond (two key) can be positioned at any position of carbochain.

[0035] in the context of the present invention, term " C _2-8-alkynyl " meaning is meant and contains 2 to 8 carbon atoms and contain one or more triple-linked side chains or straight-chain alkyl.C _2-8The illustrative example of-alkynyl comprises acetenyl, propinyl, butynyl, pentynyl, hexin base, heptyne base and octyne base and side chain form thereof.Unsaturated bond (triple bond) can be positioned at any position of carbochain.Unsaturated bond can be more than one, so C _2-8-alkynyl can be known diine of those skilled in the art or enediyne.

[0036] in the context of the present invention, term " C _3-8-cycloalkyl " comprise 3 yuan, 4 yuan, 5 yuan, 6 yuan, 7 yuan and 8 yuan of rings only containing carbon atom, and term " heterocyclic radical " meaning is meant 3 yuan, 4 yuan, 5 yuan, 6 yuan, 7 yuan and 8 yuan of rings, wherein carbon atom and 1～3 hetero atom form described ring.The hetero atom of this heterocyclic radical is independently selected from oxygen, sulfur and nitrogen.

[0037] term " heterocyclic radical " also contains one or more carbonyls or thiocarbonyl functionality, thereby makes this definition comprise O-system and sulfur-system, as lactams, lactone, cyclic imides, epithio for acid imide, cyclic carbramates etc.

[0038] C _3-8-cycloalkyl and heterocyclic radical selectively contain one or more unsaturated bonds, and this unsaturated bond exists in the mode that does not produce fragrant π-electron system.

[0039] heterocycle is selectively condensed into aromatic ring, thereby this definition comprises two ring structures.This annelated heterocycles base and the shared key of phenyl ring that selectively replaces.The example of benzo-fused heterocycle includes but not limited to benzimidazole alkane ketone, tetrahydroquinoline and methylene-dioxy benzene ring structure.

[0040] " C _3-8-cycloalkyl " exemplary example is carbocyclic ring cyclopropane, Tetramethylene., Pentamethylene., cyclopentenes, cyclopentadiene, cyclohexane extraction, cyclohexene, 1; 3-cyclohexadiene, 1; 4-cyclohexadiene, cycloheptane, cycloheptene, 1; 2-cycloheptadiene, 1; 3-cycloheptadiene, 1; 4-cycloheptadiene and 1,3,5-cycloheptatriene.

[0041] illustrative example of " heterocyclic radical " is a heterocycle tetrahydrochysene sulfo-pyrans, the 4H-pyrans, Pentamethylene oxide., piperidines, 1, the 3-dioxin, 1, the 3-diox, 1, the 4-dioxin, 1, the 4-diox, piperazine, 1,3-oxa-thiophene alkane, 1,4-oxa-sulfur glutinous rehmannia, 1,4-oxa-thiophene alkane, tetrahydrochysene-1, the 4-thiazine, 2H-1, the 2-oxazine, maleimide, butanimide, barbiturates, thiobarbituricacid, the dioxo piperazine, hydantoin, dihydrouracil, morpholine trioxane, six hydrogen-1,3, the 5-triazine, Tetramethylene sulfide, oxolane, pyrrolin, pyrrolidine, ketopyrrolidine, pyrrolidine-diones (pyrrolidione), pyrazoline, pyrazolidine, imidazoline, imidazolidine, 1, the 3-dioxole, 1, the 3-dioxolane, 1, the 3-dithiode, 1,3-dithiolane isoxazoline isoxazole alkyl oxazoline oxazolidine, thiazoline, Thiazolidine, 1, the luxuriant alkane of 3-oxa-thiophene.Can be positioned at the hetero atom place with heterocyclic the combination, or by heterocyclic carbon atom combination, or the carbon combination by benzene type ring for benzo-fused derivant.

[0042] in the context of the present invention, term " aryl " meaning is meant carbocyclic ring aromatic rings or ring system.In addition, term " aryl " comprises and condenses ring system, wherein at least two aromatic rings or at least one aryl and at least one C _3-8Shared at least one chemical bond of-cycloalkyl.The illustrative example of " aryl " ring comprises selectively the phenyl that replaces, naphthyl, phenanthryl, anthryl, tetrahydro naphthyl, fluorenyl, indenyl, and indanyl.The example of aryl is a phenyl.Term " aryl " refers to the aromatic series base, normally by a benzene type group that becomes ring carbon atom to connect, and selectively has one or more following substituent groups that are selected from: halogen, hydroxyl, amino, cyano group, nitro, alkyl amido, acyl group, C _1-6Alkoxyl, C _1-6Alkyl, C _1-6Hydroxy alkyl, C _1-6Aminoalkyl, C _1-6Alkyl amino, alkyl sulfenyl, alkyl sulphinyl, alkyl sulphonyl, sulfamoyl or trifluoromethyl.As described, aryl can be a phenyl, be more suitable for have one or two, the identical or different substituent substituted-phenyl of listing above.The position that replaces is a para-position and/or a position.The representative example of aryl includes but not limited to phenyl, 3-halogenophenyl, 4-halogenophenyl, 3-hydroxy phenyl, 4-hydroxy phenyl, 3-aminophenyl, 4-aminophenyl, 3-aminomethyl phenyl, 4-aminomethyl phenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3-cyano-phenyl, 4-cyano-phenyl, 3,5-dimethylphenyl, naphthyl, hydroxyl naphthyl, hydroxymethyl phenyl, trifluoromethyl, alkoxyl phenyl.

[0043] in the context of the present invention, term " aryl (C _1-6-alkyl) " meaning is meant and passes through C as defined above _1-6The carbocyclic ring aromatic rings that-alkyl connects.

[0044] the assorted alkyl of term aryl should be interpreted into aryl as defined above, and it passes through C _1-6-alkyl chain is connected and as substituent group, also contains the atom that at least one is selected from oxygen, sulfur and nitrogen in chain.

[0045] in the context of the present invention, term " heteroaryl " meaning is meant heterocyclic aromatic base, and wherein the one or more hetero atom that is selected from nitrogen, sulfur, phosphorus and oxygen of the one or more carbon atoms in aromatic rings replaces.

[0046] in addition, term " heteroaryl " comprises and condenses ring system, wherein at least one aromatic ring and at least one hetero-aromatic ring, at least two hetero-aromatic rings, at least one hetero-aromatic rings and at least one heterocyclic radicals or at least one hetero-aromatic ring and at least one C _3-8Shared at least one chemical bond of cycloalkyl ring.

[0047] term " heteroaryl " should be understood as that finger also contains an O or S atom or nearly four N atoms or O or S atoms and the fragrant C of the combination of two N atoms nearly _2-6Cyclic group, its replacement, and benzo and pyrido condense derivant, and become ring carbon atom to connect by one usually.Heteroaryl can have one or more following substituent groups that are selected from: halogen, hydroxyl, amino, cyano group, nitro, alkyl amido, acyl group, C _1-6-alkoxyl, C _1-6-alkyl, C _1-6-hydroxy alkyl, C _1-6-aminoalkyl, C _1-6-alkyl amino, alkyl sulfenyl, alkyl sulphinyl, alkyl sulphonyl, sulfamoyl or trifluoromethyl.Specific heteroaryl be have 0,1 or 2, be same to each other or different to each other, be selected from substituent 5 yuan and the 6 membered aromatic heterocycles system that lists above.The representation example of heteroaryl includes but not limited to unsubstituted, the derivant of single or dibasic following material: furan, benzofuran, thiophene, benzothiophene, the pyrroles, pyridine, indole oxazole benzoxazole isoxazole, benzoisoxazole, thiazole, benzothiazole, isothiazole, imidazoles, benzimidazole, pyrazoles, indazole, tetrazolium, furazan (furazan), 1,2, the 3-oxadiazole, 1,2, the 3-thiadiazoles, 1,2, the 4-thiadiazoles, triazole, benzotriazole, quinoline, isoquinolin, pyridazine, pyrimidine, purine, pyrazine, pteridine, pyrroles Fen oxazole oxazole isoxazole oxadiazole, benzopyrazoles, indazole, quinolizine, cinnolines, 2, quinazoline and quinoxaline.Modal substituent group is halogen, hydroxyl, cyano group, O-C _1-6-alkyl, C _1-6-alkyl, hydroxyl-C _1-6-alkyl, amino-C _1-6-alkyl.

[0048] term " O-C used herein _1-6-alkyl " looking like is meant C _1-6-alkoxyl (alkyloxy) or alkoxyl (alkoxy) are as methoxyl group, ethyoxyl, positive propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, amoxy, isoamoxy, neopentyl oxygen and hexyloxy.

[0049] term " halogen " comprises fluorine, chlorine, bromine and iodine.

[0050] term used herein " selectively replaces " meaning and is meant that the target group can be replaced once by one or more substituent groups or several times, as 1～5 time, 1～3 time or 1～2 time, these substituent groups are selected from C _1-6-alkyl, C _1-6-alkoxyl, oxo (it can be tautomeric enol form), carboxyl, amino, hydroxyl (when the enol system existed, it can be tautomeric ketone form), nitro, alkyl sulphonyl, alkyl sulfenyl, alkyl sulphinyl, C _1-6-alkoxy carbonyl group, C _1-6-alkyl carbonyl, formyl, single and two (C _1-6-alkyl) amino, carbamoyl, single and two (C _1-6-alkyl) amino carbonyl, amino-C _1-6-alkyl-amino carbonyl, single and two (C _1-6-alkyl) amino-C _1-6-alkyl amino-carbonyl, C _1-6-alkyl carbonyl amino, cyano group, guanidine radicals, urea groups, C _1-6-alkanoyloxy, C _1-6-alkylsulfonyloxy, dihalo-C _1-6-alkyl, three halos-C _1-6-alkyl and halogen.Usually, above-mentioned substituent group can also selectively be replaced.

[0051] term " salt " meaning is meant pharmaceutically acceptable acid addition salts, it can be with the functional group of suitable acid treatment alkali form such as ammonia and obtains, and suitable acid for example is mineral acid, as halogen acids, normally hydrochloric acid, hydrobromic acid, Fluohydric acid. or hydroiodic acid, sulphuric acid, nitric acid, phosphoric acid etc.; Or organic acid, as acetic acid, propanoic acid, glycolic, 2-ethylene lactic acid, 2-oxygen propanoic acid, ethanedioic acid, malonic acid, succinic acid, (Z)-2-butylene diacid, maleic acid, 2-oxysuccinic acid, 2,3-desoxalic acid, 2-hydroxyl-1,2,3-tricarballylic acid, methanesulfonic acid, ethyl sulfonic acid, benzenesulfonic acid, 4-toluene sulfonic acide, cyclohexylsulfamic acid, 2-Para Hydroxy Benzoic Acid, 4-amino-2-Para Hydroxy Benzoic Acid and known other acid of those skilled in the art.

[0052] method of the present invention relates to the adjusting of cholinoceptor.Usually, described cholinoceptor is a muscarinic receptor; An example of cholinoceptor is M ₁The muscarinic receptor of-receptor subtype.Can find out that from embodiment in the embodiment that is fit to, cholinoceptor can be muscarinic M ₁-receptor and muscarinic M ₄-receptor subtype one or both of has.Common and the M of the useful reaction of physiology in the inventive method ₁-receptor subtype is with respect to M ₂Or M ₃-receptor subtype specific, activated relevant is perhaps with M ₁-and M ₄-receptor subtype is with respect to M ₂Or M ₃-receptor subtype specific, activated relevant.In addition, the useful reaction of the physiology in the inventive method is usually relevant with the agonist activity of the chemical compound of general formula I or IA.Thereby in one embodiment, the chemical compound of general formula I or IA is a muscarinic agonist, as M ₁Agonist or M ₁And M ₄Agonist.

[0053] another aspect of the present invention relates to the method that improves cholinergic receptor activity.In one embodiment, method comprises that the system that makes cholinoceptor or contain cholinoceptor contacts with at least a general formula I as defined above of effective dose or the chemical compound of IA.

[0054] related fields of the present invention relate to a kind of treatment or prevention or alleviate one or more and the method for mammal such as people's not normal relevant symptom.In one embodiment, method comprises the general formula I of effective dose or the compound administration of IA, and is described not normal relevant with muscarinic receptor, for example with M ₁The muscarinic receptor hypotype is relevant.

[0055] and M ₁The not normal normally Mental Subnormality that the muscarinic receptor hypotype is relevant.Being fit to Mental Subnormality with the inventive method treatment is selected from cognitive impairment, forgetful, confusion, memory loss, attention disappearance, the blindness, depression, pain, sleep disordered, psychosis and intraocular pressure and increases.

[0056] and M ₁The not normal not necessarily Mental Subnormality that the muscarinic receptor hypotype is relevant.For example intraocular pressure increases and M ₁The muscarinic receptor hypotype is relevant.What therefore, the inventive method related to not normally comprises non-Mental Subnormality.

[0057] the inventive method relate to not normal also can be selected from nerve degeneration relevant disease, Alzheimer disease, Parkinson's disease, schizophrenia, Huntington chorea, family ataxia, Ji Liedela tell auspicious syndrome, Down's syndrome, Niemann-Pick disease, dementia, clinical melancholia, with age cognitive decline, attention deficiency, sudden infant death syndrome and glaucoma relatively.

[0058] as mentioned above, chemical compound of the present invention is to muscarinic M ₁Receptor subtype has high selectivity and affinity.Can find out that from embodiment chemical compound is to M ₁And M ₄Receptor subtype one or both of all has high affinity, and with other receptor such as M ₂, M ₃And M ₅Receptor subtype is compared has high selectivity.Chemical compound of the present invention is usually at least in part as M ₁Agonist or as M ₁And M ₄Agonist.

[0059] chemical compound of the present invention is also to dopamine D ₂Receptor has affinity.The dopamine hypothesis relevant with schizophrenia as discussed above, the chemical compound of useful as muscarinic agonist and dopamine antagonist is crucial for the multiple Mental Subnormality of abundant treatment simultaneously.Thereby the present invention also relates to use the non compos mentis method of compounds for treating of the present invention, described chemical compound is as D ₂Antagonist or D ₂Inverse agonist and muscarinic agonist are especially as M ₁Agonist or M ₁And M ₄Agonist.Method of the present invention like this can be treated the disease in the Mental Subnormality, and wherein the useful reaction of physiology is because to M ₁Agonism, M ₁And M ₄Agonism, M ₁Agonism and D ₂Antagonism or M ₁And M ₄Agonism and D ₂The adjusting of antagonism.

[0060] in one aspect of the invention, chemical compound of the present invention is a psychosis, and described antipsychotic activity is because chemical compound of the present invention can be used as M ₁Agonist or M ₁And M ₄Agonist or as M ₁Agonist and D ₂Antagonist or M ₁And M ₄Agonist and D ₂Antagonist.

[0061] the another aspect of the present invention pharmaceutical composition that relates to chemical compound or its pharmaceutically acceptable salt of general formula I A or contain any above-mentioned substance is used for the treatment of purposes in disease relevant with cholinoceptor or its part or the not normal medicine in preparation.This medicine can be used for treating relevant with receptor as discussed above disease or not normal as discussed above.Related fields of the present invention relate to a kind of pharmaceutical composition, pharmaceutical composition and pharmaceutically acceptable carrier or excipient that it contains chemical compound, its pharmaceutically acceptable salt, its stereoisomer of the general formula I as defined above of effective dose or contains any above-mentioned substance.

[0062] the invention provides noval chemical compound shown in the general formula I and salt thereof and isomer

M is 0,1 or 2;

C ₃-C ₄Be CH ₂-CH or CH=C, perhaps C ₄Be CH and C ₃Do not exist;

R ⁴And R ⁵In each C that is independently selected from hydrogen, halogen, hydroxyl, selectively replaces _1-6-alkyl, O-C _1-6Alkyl, aryl-C _1-6Alkyl and the aryl alkyl of mixing;

Y is selected from O, S and H ₂

X is a divalent group, and it is selected from-C (R ⁶) (R ⁷)-C (R ⁶) (R ⁷)-,-C (R ⁶)=C (R ⁷)-,-O-C (R ⁶) (R ⁷)-, C (R ⁶) (R ⁷)-O-,-S-C (R ⁶) (R ⁷)-,-C (R ⁶) (R ⁷)-S-,-N (R ^N)-C (R ⁶) (R ⁷)-,-C (R ⁶) (R ⁷)-N (R ^N)-,-C (R ⁶) (R ⁷)-C (R ⁶) (R ⁷)-C (R ⁶) (R ⁷)-,-O-C (R ⁶) (R ⁷)-C (R ⁶) (R ⁷)-, S-C (R ⁶) (R ⁷)-C (R ⁶) (R ⁷)-, N (R ^N)-C (R ⁶) (R ⁷)-C (R ⁶) (R ⁷)-,-C (R ⁶) (R ⁷)-C (R ⁶) (R ⁷)-O ,-C (R ⁶) (R ⁷)-C (R ⁶) (R ⁷)-S ,-C (R ⁶) (R ⁷)-C (R ⁶) (R ⁷)-N (R ^N)-,-C (R ⁶) (R ⁷)-C (R ⁶)=C (R ⁷)-and-C (R ⁶)=C (R ⁷)-C (R ⁶) (R ⁷), R wherein ⁶And R ⁷Be independently selected from hydrogen, halogen, hydroxyl, nitro, cyano group, NR ^NR ^N, N (R ^N)-C (O) N (R ^N), the C that selectively replaces _1-6-alkyl, C _2-6-thiazolinyl, C _2-6-alkynyl, the O-C that selectively replaces _1-6The O-aryl of-alkyl, selectively replacement, the O-C that selectively replaces _2-6-thiazolinyl, the O-C that selectively replaces _2-6-alkynyl,

[0063] researcher of the present invention finds that chemical compound of the present invention is to M ₁Muscarinic receptor has high affinity and specificity.Chemical compound of the present invention also is used for a series of and M ₁In the disease that the adjusting of muscarinic receptor hypotype is correlated with.

[0064] usually, R in the chemical compound of general formula I ¹Be selected from the C that selectively replaces _1-6-alkyl, the C that selectively replaces _1-6-alkylidene, the C that selectively replaces _2-6-thiazolinyl, the C that selectively replaces _2-6-alkynyl, the O-C that selectively replaces _1-6-alkyl and the O-C that selectively replaces _2-6-thiazolinyl.R ¹Can be selected from the C that selectively replaces _1-6-alkyl, the C that selectively replaces _1-6-alkylidene, the C that selectively replaces _2-6-thiazolinyl and the O-C that selectively replaces _1-6-alkyl.R ¹Usually can be selected from the C that selectively replaces _1-6-alkyl, the C that selectively replaces _1-6-alkylidene and the O-C that selectively replaces _1-6-alkyl.The most usually, R ¹Be selected from the C that selectively replaces ₄-alkyl, the C that selectively replaces ₅-alkyl, the C that selectively replaces ₄-alkylidene and the O-C that selectively replaces _1-6-alkyl.In preferred embodiments, R ¹Can be unsubstituted C ₄-alkyl, unsubstituted C ₅-alkyl or unsubstituted O-C ₃-alkyl is as normal-butyl, n-pentyl or positive propoxy.

[0065] in the special embodiment of the present invention, R in the chemical compound of general formula I ¹Be the C that selectively replaces _1-6-alkyl, it is selected from unsubstituted C _1-6-alkyl and C _1-6-alkoxyalkyl.C _1-6-alkoxyalkyl can be C _1-3-alkoxy C _1-3Alkyl.Usually, C _1-6-alkoxyalkyl is selected from methoxy-propyl, ethoxyethyl group, propoxyl group methyl and methoxy ethyl.

[0066] in one embodiment of the invention, the chemical compound of general formula I is piperidines, bicyclo-piperidines, the undersaturated piperidines of 3-4-or the undersaturated piperidines of bicyclo-3-4-.In this embodiment, C ₃-C ₄Key can be a singly-bound, thereby forms piperidine ring or bicyclo-piperidines.Selectively, piperidines can be that 3-4 is undersaturated.Be C ₃-C ₄Can be two key (C ₃=C ₄), thereby form undersaturated piperidines of 3-4-or the undersaturated piperidines of bicyclo-3-4-.

[0067] in another embodiment of the invention, m is 0, C ₃Do not exist, simultaneously C ₄Be CH, thereby form the azetidine ring.Two ring analogues that also comprise azetidine.

[0068] in selectable embodiment, m is 0, thereby works as C ₃-C ₄Form pyrrolidine ring or 3-pyrrolin when being singly-bound or two key respectively.Two ring analogues that also comprise pyrrolidine ring or 3-pyrrolin.In being more suitable for, m is 2, thereby forms 7 yuan of rings.In specific embodiment, m is 1.

[0069] in one embodiment, R ²And R ³Form the bicyclo-ring system together, thereby

Be selected from

R wherein ⁸Occur 0,1 or 2 time, and be independently selected from the C that selectively replaces _1-6Alkyl, the O-C that selectively replaces _1-6Alkyl, halogen, hydroxyl.

[0070] in this embodiment, preferably select R ²And R ³Make R ²And R ³Form ring system together, thereby

Be selected from

[0071] in a more preferred embodiment, select substituent R ²And R ³Make that dicyclo is 8-azabicyclo [3.2.1] octane that 3-replaces.

[0072] yet, in special embodiment, R ²And R ³The C that be independently selected from hydrogen, selectively replaces _1-6Alkyl, the O-C that selectively replaces _1-6Alkyl, halogen and hydroxyl.

[0073] thereby, in the combination of the embodiment of the chemical compound of general formula I, C ₃-C ₄Be singly-bound, R ²And R ³The C that be independently selected from hydrogen, selectively replaces _1-6Alkyl, the O-C that selectively replaces _1-6Alkyl, halogen and hydroxyl, m are 1.Preferably, R ²And R ³Be hydrogen.

[0074] in another combination, m can be 0, C ₃Can there be C ₄But CH, thereby

Be

[0075] in another combination of embodiment, C ₃-C ₄Make to form piperidine ring with m, for example R wherein ²And R ³Be hydrogen.In other embodiment, C ₃-C ₄With feasible piperidine ring, the R of forming of m ²And R ³Be hydrogen, R ¹Be unsubstituted C ₄-alkyl, unsubstituted C ₅-alkyl or O-C ₃-alkyl is as butyl, amyl group or propoxyl group.

[0076] thereby, in one embodiment,

It is the 4-butyl piperidine.

[0077] in another embodiment,

It is the 4-butyl piperidine.

[0078] in one embodiment of the invention, C ₃-C ₄With the feasible azetidine ring that forms of m,

[0079] R ²And R ³Be hydrogen, R ¹Be selected from unsubstituted C ₄-alkyl, unsubstituted C ₅-alkyl and O-C ₃-alkyl.Thereby, in one embodiment,

It is 4-butyl azetidine.

[0080] in one aspect of the invention, two nitrogen-atoms of two ring systems of the chemical compound of the chain of 3 carbon connection general formula I.Researcher of the present invention finds that this propylidene that selectively replaces can make chemical compound have efficiently ability in conjunction with cholinoceptor in the unit at interval.More specifically, chemical compound of the present invention shows agonist character to cholinoceptor, especially to muscarinic receptor.

[0081] in one embodiment, chain

Be unsubstituted, the meaning is meant all R ⁴And R ⁵All be hydrogen.

[0082] in another embodiment, substituent R ⁴In one be selected from C _1-6-alkyl, O-C _1-6-alkyl and halogen, and substituent R ⁴In in addition two be hydrogen.

[0083] in a combination of embodiment, substituent R ⁴In one be selected from C _1-6-alkyl, O-C _1-6-alkyl and halogen, and substituent R ⁴In in addition two be hydrogen, and all R ⁵All be hydrogen.

[0084] in preferred embodiments, substituent R ⁴In one be selected from methyl, methoxyl group, ethyl and fluorine, and remaining R ⁴And R ⁵All be hydrogen.

[0085] usually, work as substituent R ⁴In one be C _1-6-alkyl, O-C _1-6When-alkyl or halogen, this chain is a 2-replacement-trimethylene.

[0086] in the embodiment that is more suitable for, this chain is 2,2-is dibasic-and trimethylene, wherein R ⁴In one and R ⁵In a C normally _1-6-alkyl or fluorine.

[0087] in certain embodiments of the invention, this propylidene chain has one or more substituent groups, and contains the stereoisomerism atom in the propylidene chain.As listed among the embodiment, this chipal compounds is raceme or enantiomeric form preferably.Comprise pure enantiomer and raceme in the present invention.

[0088] X can be the straight chain unit of 1-, 2-or 3-atom, and its atom in the ring that contains X forms 5 yuan, 6 yuan or 7 yuan of rings.As mentioned above, the X in the ring is a divalent group, and it is selected from-C (R ⁶) (R ⁷)-C (R ⁶) (R ⁷)-,-C (R ⁶)=C (R ⁷)-,-O-C (R ⁶) (R ⁷)-, C (R ⁶) (R ⁷)-O-,-S-C (R ⁶) (R ⁷)-,-C (R ⁶) (R ⁷)-S-,-N (R ^N)-C (R ⁶) (R ⁷)-,-C (R ⁶) (R ⁷)-N (R ^N)-,-C (R ⁶) (R ⁷)-C (R ⁶) (R ⁷)-C (R ⁶) (R ⁷)-,-O-C (R ⁶) (R ⁷)-C (R ⁶) (R ⁷)-, S-C (R ⁶) (R ⁷)-C (R ⁶) (R ⁷)-, N (R ^N)-C (R ⁶) (R ⁷)-C (R ⁶) (R ⁷)-,-C (R ⁶) (R ⁷)-C (R ⁶) (R ⁷)-O ,-C (R ⁶) (R ⁷)-C (R ⁶) (R ⁷)-S ,-C (R ⁶) (R ⁷)-C (R ⁶) (R ⁷)-N (R ^N)-,-C (R ⁶) (R ⁷)-CH=CH-reaches-CH=CH-C (R ⁶) (R ⁷).

[0089] in preferred embodiments, X is selected from-C (R ⁶) (R ⁷)-C (R ⁶) (R ⁷)-,-C (R ⁶)=C (R ⁷)-,-O-C (R ⁶) (R ⁷)-, C (R ⁶) (R ⁸)-O-,-S-C (R ⁶) (R ⁷)-,-C (R ⁶) (R ⁷)-S-,-N (R ^N)-C (R ⁶) (R ⁷)-,-C (R ⁶) (R ⁷)-N (R ^N)-.

[0090] in a more preferred embodiment, X is selected from-C (R ⁶) (R ⁷)-C (R ⁶) (R ⁷)-,-O-C (R ⁶) (R ⁷)-, C (R ⁶) (R ⁸)-O-and-C (R ⁶)=C (R ⁷)-.

[0091] R ⁶And R ⁷It is the selectable substituent group of ring system.Researcher of the present invention can be expected a series of substituent groups, and this also is known for those skilled in the art.Substituent R ⁶And R ⁷Can be independently selected from hydrogen, halogen, hydroxyl, nitro, cyano group, NR ^NR ^N, N (R ^N)-C (O) N (R ^N), the C that selectively replaces _1-6-alkyl, C _2-6-thiazolinyl, C _2-6-alkynyl, the O-C that selectively replaces _1-6The O-aryl of-alkyl, selectively replacement, the O-C that selectively replaces _2-6-thiazolinyl, the O-C that selectively replaces _2-6-alkynyl.

[0092] preferably, work as substituent R ⁶And R ⁷When being present among the defined X, they are selected from hydrogen, halogen, hydroxyl and C usually _1-6-alkyl.More generally, work as R ⁶And R ⁷When constituting defined X a part of, they all are hydrogen.

[0093] in one embodiment, Y is selected from O, S and H ₂

[0094] in preferred embodiments, Y is O.

[0095] as mentioned above, L ¹And L ²Be divalent group, it is independently selected from-C (R ⁷)=C (R ⁸) ,-C (R ⁷)=N-,-N=C (R ⁷)-,-S-,-NH-and-O-; L wherein ¹And L ²In only have one and can be selected from-S-and-O-.Usually, L ¹And L ²Make

Be fragrance or assorted aromatic rings.In one embodiment, L ¹And L ²Be independently selected from-C (R ⁶)=C (R ⁷) ,-C (R ⁶)=N-,-N=C (R ⁷)-and-S-, wherein L ¹And L ²In only have one to be-S-.In another embodiment, L ¹And L ²In at least one be C (R ⁶)=C (R ⁷).In another embodiment, L ¹And L ²Make and form 6 yuan of rings.In another embodiment, L ¹And L ²All be-C (R ⁶)=C (R ⁷)-.

[0096] preferably, work as substituent R ⁶And R ⁷Be present in defined

When middle, they are selected from hydrogen, halogen, hydroxyl, C usually _1-6-alkyl and O-C _1-6-alkyl.

[0097] preferably, work as substituent R ⁶And R ⁷Be present in defined

When middle, they are selected from hydrogen, fluorine, chlorine, methyl and methoxyl group.

[0098] therefore, in a combination of embodiment, shown in the following general formula I a of chemical compound of the present invention

R wherein ¹Be selected from the C that selectively replaces _1-6-alkyl, the C that selectively replaces _1-6-alkylidene, the C that selectively replaces _2-6-thiazolinyl, the C that selectively replaces _2-6-alkynyl, the O-C that selectively replaces _1-6-alkyl and the O-C that selectively replaces _2-6-thiazolinyl; And R ², R ³, R ⁴, X, Y, R ⁶And R ⁷Press as defined above.

[0099] in another combination of embodiment, chemical compound of the present invention is shown in general formula I a, and wherein X is selected from-C (R ⁶) (R ⁷)-C (R ⁶) (R ⁷)-,-C (R ⁶)=C (R ⁷)-,-O-C (R ⁶) (R ⁷)-, C (R ⁶) (R ⁸)-O-,-S-C (R ⁶) (R ⁷)-,-C (R ⁶) (R ⁷)-S-,-N (R ^N)-C (R ⁶) (R ⁷)-,-C (R ⁶) (R ⁷)-N (R ^N)-, be R wherein ⁶And R ⁷Be preferably hydrogen.

[0100] in another combination of embodiment, chemical compound of the present invention is shown in general formula I a, and wherein Y is O.

[0101] in another combination of embodiment, chemical compound of the present invention shown in general formula I a, R wherein ⁴Be selected from hydrogen, C _1-6-alkyl, O-C _1-6-alkyl and halogen.

[0102] in another combination of embodiment, chemical compound of the present invention shown in general formula I a, R wherein ⁶And R ⁷Be selected from hydrogen, halogen, hydroxyl, C _1-6-alkyl and O-C _1-6-alkyl.

[0103] in another combination of embodiment, chemical compound of the present invention shown in general formula I a, the C that selectively replaces wherein _1-6-alkyl is selected from unsubstituted C _1-6-alkyl and C _1-6-alkoxyalkyl, wherein Y is selected from O and H ₂, wherein X is selected from-C (R ⁶) (R ⁷)-C (R ⁶) (R ⁷)-,-C (R ⁶)=C (R ⁷)-,-O-C (R ⁶) (R ⁷)-, C (R ⁶) (R ⁷)-O-,-S-C (R ⁶) (R ⁷)-,-C (R ⁶) (R ⁷)-S-, wherein L ¹And L ²Be independently selected from-C (R ⁶)=C (R ⁷)-,-C (R ⁶)=N-and-N=C (R ⁷)-, reaches wherein R ⁴The C that be selected from hydrogen, halogen, hydroxyl, selectively replaces _1-6-alkyl and the O-C that selectively replaces _1-6Alkyl.

[0104] in another combination of embodiment, and the 1-[3-that chemical compound of the present invention selectively replaces (propyl group of 4-Alkylpiperidine base-1-)]-1,2,3, the 4-tetrahydroquinoline; Selectively the 1-[3-of Qu Daiing (propyl group of 4-Alkylpiperidine base-1-)]-3,4-dihydro-1H-quinoline-2-one-; Selectively the 1-[3-of Qu Daiing (propyl group of 4-Alkylpiperidine base-1-)]-the 1H-quinoline-2-one-; Selectively the 4-[3-of Qu Daiing (propyl group of 4-Alkylpiperidine base-1-)]-4H-benzo [1,4] oxazine-3-ketone; Selectively the 4-[3-of Qu Daiing (propyl group of 4-Alkylpiperidine base-1-)]-4H-benzo [1,4] thiazine-3-ketone; Selectively the 1-[3-of Qu Daiing (propyl group of 3-alkyl-8-azabicyclo [3.2.1] octyl group-8-)]-1,2,3, the 4-tetrahydroquinoline; Selectively the 1-[3-of Qu Daiing (propyl group of 3-alkyl-8-azabicyclo [3.2.1] octyl group-8-)]-3,4-dihydro-1H-quinoline-2-one-; Selectively the 1-[3-of Qu Daiing (propyl group of 3-alkyl-8-azabicyclo [3.2.1] octyl group-8-)]-the 1H-quinoline-2-one-; Selectively the 4-[3-of Qu Daiing (propyl group of 3-alkyl-8-azabicyclo [3.2.1] octyl group-8-)]-4H-benzo [1,4] oxazine-3-ketone; Selectively the 4-[3-of Qu Daiing (propyl group of 3-alkyl-8-azabicyclo [3.2.1] octyl group-8-)]-4H-benzo [1,4] thiazine-3-ketone; Selectively the 1-[3-of Qu Daiing (propyl group of 3-alkyl azetidine-1-)]-3,4-dihydro-1H-quinoline-2-one-; Selectively the 1-[3-of Qu Daiing (propyl group of 3-alkyl azetidine-1-)]-the 1H-quinoline-2-one-; Selectively the 1-[3-of Qu Daiing (propyl group of 3-alkyl azetidine-1-)]-1,2,3, the 4-tetrahydroquinoline; Selectively the 4-[3-of Qu Daiing (propyl group of 3-alkyl azetidine-1-)]-4H-benzo [1,4] oxazine-3-ketone; Selectively the 4-[3-of Qu Daiing (propyl group of 3-alkyl azetidine-1-)]-4H-benzo [1,4] thiazine-3-ketone.

[0105] The present invention is suitable for embodiments of the compound may be selected from 1 - [3 - (4 - butyl - piperidinyl -1) - Propyl] -1,2,3,4 - tetrahydro - quinoline; 1 - [3 - (4 - butyl - piperidin-1) - propyl] -2 - methyl-1 , 2,3,4 - Tetrahydro - quinoline; 1 - [3 - (4 - butyl - piperidin-1) - propyl] -6 - methyl-1, 2,3,4 - tetrahydro - quinoline; 1 - [3 - (4 - butyl - piperidin-1) - propyl]-8 - methyl-1, 2,3,4 - tetrahydro - quinoline; 1 - [3 - (4 - D Base - piperazine Piperidine-1) - propyl]-7 - fluoro-2 - methyl-1, 2,3,4 - tetrahydro - quinoline; 1 - [3 - (4 - butyl - piperidin-1) - C Yl]-7 - trifluoromethyl-1, 2,3,4 - tetrahydro - quinoline; 1 - [3 - (4 - butyl - piperidin-1) - propyl] -3,4 - dihydro- -1H-quinolin-2 - one; 1 - [3 - (4 - butyl - piperidin-1) - propyl] -6 - methoxy-3 ,4 - dihydro-1H-quinolin- -2 - One; 4 - [3 - (4 - butyl - piperidin-1) - propyl]-4H-benzo [1,4] thiazine-3 - one; 4 - [3 - (4 - butyl - Piperidin-1) - propyl]-4H-benzo [1,4] oxazin-3 - one; 4 - [3 - (4 - butyl - piperidin-1) - propyl] -6 - Methyl-4H-benzo [1,4] oxazin-3 - one; 6 - acetyl-4 - [3 - (4 - butyl - piperidin-1) - propyl]-4H- Benzo [1,4] oxazin-3 - one; 4 - [3 - (4 - butyl - piperidin-1) - propyl]-6 - methyl -3,4 - dihydro-2H- benzene And [1,4] oxazine; 4 - [3 - (4 - butyl - piperidin-1) - propyl] -6 - ethyl-3 ,4 - dihydro-2H-benzo [1, 4] Oxazine; (R) -4 - [3 - (4 - piperidin-1-butyl) -2 - methyl-propyl]-4H-benzo [1,4] thiazine-3 - one; (R) -4 - [2 - methyl-3 - (4 - propoxy-piperidin-1 -) propyl]-4H-benzo [1,4] thiazine-3 - one; (R) -4 - [3 - (4 - butylene - piperidin-1)-2 - methyl - propyl]-4H-benzo [1,4] thiazine-3 - one; (R) -4 - [3 - (3 - butyl-8 - aza - bicyclo [3.2.1] octyl -8) -2 - methyl - propyl]-4H-benzo [1,4] thiophene -3 - one; (R) -4 - [2 - methyl-3 - (3 - pentyl-8 - aza - bicyclo [3.2.1] octyl -60 -) propyl]-4H-phenyl And [1,4] thiazine-3 - one; 4 - [3 - (4 - butyl-piperidin-1 -) propyl] -6,8 - dichloro-7 - methyl-4H-benzo [1,4] oxazin-3 - one; 4 - [3 - (4 - butyl - piperidin-1 -) propyl] -6,8 - dimethyl-4H-benzo [1,4 ] evil -3 - one (81MF2237F); 6 - tert-butyl-4 - [3 - (4 - butyl - piperidin-1 -) propyl]-4H-benzo [1,4] oxazin-3 - one; 4 - [3 - (4 - butyl-piperidin-1 -) propyl] -5 - methyl-4H-benzo [1,4] oxazin - 3 - Ketone; 4 - [3 - (4 - butyl-piperidin-1 -) propyl]-7 - methyl-4H-benzo [1,4] oxazin-3 - one; 4 - [3 - ( 4 - Butyl-piperidin-1 -) propyl]-6 - chloro-7 - nitro-4H-benzo [1,4] oxazin-3 - one; 4 - [3 - (4 - butyl piperazine Piperidine-1 -) propyl]-7 - chloro-4H-benzo [1,4] oxazin-3 - one; 4 - [3 - (4 - butyl-piperidin-1 -) C Yl] -6 - fluoro-4H-benzo [1,4] oxazin-3 - one; 4 - [3 - (4 - butyl-piperidin-1 -) propyl] -7,8 - difluoro- -4H-benzo [1,4] oxazin-3 - one; 4 - [3 - (4 - butyl-piperidin-1 -) propyl]-4H-pyrido [4,3-b] [1,4] thiazine-3 - one; 4 - [3 - (4 - propoxy-piperidin-1 -) propyl]-4H-benzo [1,4] thiazide 3 - one; 4 - [3 - (4 - propoxy-piperidin-1 -) propyl]-4H-benzo [1,4] oxazin-3 - one; 4 - [3 - (4 - D Piperidin-1 -) propyl]-7 - fluoro-4H-benzo [1,4] oxazin-3 - one; 4 - [3 - (4 - butylene piperidin-1 -) Propyl]-4H-benzo [1,4] thiazine-3 - one; 4 - [3 - (4 - butylene piperidin-1 -) propyl]-4H-benzo [1,4] Oxazin-3 - one; 4 - [3 - (3 - butylene -8 - aza - bicyclo [3.2.1] octyl -8) - propyl]-4H-benzo [1,4] Oxazin-3 - one; 4 - [3 - (4 - butyl-piperidin-1 -) propyl] -6 - methoxy-4H-benzo [1,4] oxazin-3 - one; 4 - [3 - (4 - butyl-piperidin-1 -) propyl] -6,8 - dichloro-7 - ethyl-4H-benzo [1,4] oxazin-3 - one; 4 - [3 - (4 - butyl-piperidin-1 -) propyl]-8 - fluoro-4H-benzo [1,4] oxazin-3 - one; 6 - bromo-4 - [3 - (4 - D Piperidin-1 -) propyl]-8 - fluoro-4H-benzo [1,4] oxazin-3 - one; 4 - [3 - (4 - butyl-piperidin-1 -) C Yl]-8 - isopropyl-4H-benzo [1,4] oxazin-3 - one; (R, S) -4 - [3 - (4 - piperidin-1-butyl) -2 - hydroxy Propyl] -6 - methyl-4H-benzo [1,4] oxazin-3 - one; (R, S) -4 - [3 - (4 - piperidin-1-butyl) -2 - hydroxy Propyl]-4H-benzo [1,4] oxazin-3 - one; (-) -4 - [3 - (4 - piperidin-1-butyl) -2 - hydroxy-propyl]-4H- Benzo [1,4] oxazin-3 - one; (R, S) -4 - [3 - (4 - piperidin-butyl) -2 - methoxy-propyl]-4H-benzo [1, 4] Oxazin-3 - one; (R, S) -4 - [2 - hydroxy - 3 - (3 - pentyl-bicyclo [3.2.1] octyl -8) - propyl]-4H-benzo [1,4] oxazin-3 - one; 4 - [2 - (4 - butyl-piperidin-1 - methyl) allyl]-4H-benzo [1,4] oxazin-3 - Ketone; (R, S) -4 - [3 - (4 - piperidinyl-1-butyl) -2 - fluoro-propyl]-4H-benzo [1,4] oxazin-3 - one; (S) -4 - [3 - (4 - butyl - piperidin-1)-2 - methyl - propyl]-4H-benzo [1,4] oxazin-3 - one; (R) -4 - [3 - (4 - piperidin-1-butyl) -2 - methyl-propyl]-4H-benzo [1,4] oxazin-3 - one; (R) -4 - [1 - Methyl-3 - (4 - piperidin-1-propoxy) - propyl]-4H-benzo [1,4] oxazin-3 - one; (R) -4 - [3 - (4 - inferior Piperidin-1-butyl) -2 - methyl-propyl]-4H-benzo [1,4] oxazin-3 - one; (R) -4 - [3 - (3 - butyl-8 - nitrogen Miscellaneous - bicyclo [3.2.1] octyl -8) -2 - methyl-propyl]-4H-benzo [1,4] oxazin-3 - one; (R) -4 - [2 - methyl- -3 - (3 - pentyl-8 - aza-bicyclo [3.2.1] octyl -60 -) propyl]-4H-benzo [1,4] oxazin-3 - one; (R) -6 - Fluoro-4 - [2 - methyl -3 - (4 - propoxy - piperidin-1) - propyl]-4H-benzo [1,4] oxazin-3 - one; (R) -4 - [3 - (4 - piperidin-1-butylene)-2 - methyl - propyl]-6 - fluoro-4H-benzo [1,4] oxazin-3 - one; (R) -4 - [3 - (4 - piperidin-1-butyl) -2 - methyl-propyl]-6 - fluoro-4H-benzo [1,4] oxazin-3 - one; (R) -4 - [3 - (3 - butyl-8 - aza-bicyclo [3.2.1] octyl -8) -2 - methyl-propyl]-6 - fluoro-4H-benzo [1, 4] Oxazin-3 - one; (R) -6 - fluoro-4 - [2 - methyl -3 - (3 - pentyl-8 - aza-bicyclo [3.2.1] octyl -8) - C Yl]-4H-benzo [1,4] oxazin-3 - one; (R) -4 - [3 - (4 - butyl-piperidin-1 -) 2 - methyl-propyl]-7 - fluorine -4H-benzo [1,4] oxazin-3 - one; (R) -7 - fluoro-4 - [2 - methyl -3 - (4 - propoxy-piperidin-1 -) C Yl]-4H-benzo [1,4] oxazin-3 - one; (R) -4 - [3 - (4 - butylene-1 piperidinyl) -2 - methyl-propyl]-7 - Fluoro-4H-benzo [1,4] oxazin-3 - one; (R) -4 - [3 - (3 - butyl-8 - aza-bicyclo [3.2.1] octyl -8) -2 - Methyl-propyl]-7 - fluoro-4H-benzo [1,4] oxazin-3 - one; (R) -7 - fluoro-4 - [2 - methyl -3 - (3 - pentyl - 8 - Nitrogen Azabicyclo [3.2.1] octyl -8) - propyl]-4H-benzo [1,4] oxazin-3 - one; (R) -4 - [3 - (4 - butyl-piperidine -1) - 2 - methyl - propyl] -6 - methoxy-4H-benzo [1,4] oxazin-3 - one; (R) -4 - [3 - (4 - butylene Piperidin-1) -2 - methyl-propyl] -6 - methoxy-4H-benzo [1,4] oxazin-3 - one; (R) -4 - [3 - (3 - D base -8 - Azabicyclo [3.2.1] octyl -8) -2 - methyl-propyl] -6 - methoxy-4H-benzo [1,4] oxazin-3 - one; (R) -6 - methoxy-4 - [2 - methyl -3 - (3 - pentyl-8 - aza - bicyclo [3.2.1] octyl -60 -) propyl]-4H-phenyl And [1,4] oxazin-3 - one; (R) -6 - methoxy-4 - [2 - methyl -3 - (4 - propoxy-piperidin-1 -) C Yl]-4H-benzo [1,4] oxazin-3 - one; (R) -6 - methyl-4 - [2 - methyl -3 - (4 - piperidin-1-propoxy) - Propyl]-4H-benzo [1,4] oxazin-3 - one; (R) -4 - [3 - (4 - butylene-1 piperidinyl) -2 - methyl-propyl Yl] -6 - methyl-4H-benzo [1,4] oxazin-3 - one; (R) -4 - [3 - (4 - piperidin-1-butyl) -2 - methyl-C Yl] -6 - methyl-4H-benzo [1,4] oxazin-3 - one; (R) -4 - [3 - (3 - butyl-8 - azabicyclo [3.2.1] oct- -8) -2 - methyl-propyl] -6 - methyl-4H-benzo [1,4] oxazin-3 - one; (R) -4 - [3 - (3 - pentyl-8 - aza Bicyclo [3.2.1] octyl -8) -2 - methyl-propyl] -6 - methyl-4H-benzo [1,4] oxazin-3 - one; 1 - [3 - (4 - C Piperidin-oxy-1 -) propyl] -3,4 - dihydro-1H-quinolin-2 - one; 1 - [3 - (4 - butyl-piperidin-1 -) C Yl] -6 - fluoro-3 ,4 - dihydro-1H-quinolin-2 - one; 6 - fluoro-1 - [3 - (4 - propoxy-piperidin-1 -) propyl] -3 4 - Dihydro-1H-quinolin-2 - one; (R, S) -1 - [3 - (4 - piperidin-1-butyl) -2 - methyl-propyl]-6 - fluoro-3 ,4 - two Hydrogen-1H-quinolin-2 - one; (R, S) -6 - fluoro-1 - [3 - (4 - piperidinyl-1-propoxy) -2 - methyl-propyl] -3,4 - two Hydrogen-1H-quinolin-2 - one; 1 - [3 - (4 - butyl-piperidin-1 -) propyl]-6 - chloro -3,4 - dihydro-1H-quinolin-2 - One; 1 - [3 - (4 - piperidin-1-butyl -) propyl] -6 - methyl-3 ,4 - dihydro-1H-quinolin-2 - one; 6 - methyl 1 - [3 - (4 - propoxy-piperidin-1 -) propyl] -3,4 - dihydro-1H-quinolin-2 - one; 1 - [3 - (4 - butyl piperazine pyridine -1 -) propyl]-7 - fluoro-3 ,4 - dihydro-1H-quinolin-2 - one; 1 - [3 - (4 - butyl-piperidin-1 -) propyl] - 5 - Methyl -3,4 - dihydro-1H-quinolin-2 - one; 1 - [3 - (4 - butyl-piperidin-1 -) propyl]-7 - methyl -3,4 - Hydrogen-1H-quinolin-2 - one; 1 - [3 - (4 - butyl-piperidin-1 -) propyl]-7 - fluoro-6 - methyl -3,4 - dihydro-1H- Quinolin-2 - one; 1 - [3 - (4 - butyl-piperidin-1 -) propyl] -6,7 - difluoro-3 ,4 - dihydro-1H-quinolin-2 - one ; 6,7 - difluoro-1 - [3 - (4 - propoxy-piperidin-1 -) propyl] -3,4 - dihydro-1H-quinolin-2 - one; (R, S) -1 - [3 - (4 - piperidin-1-butyl) -2 - methyl-propyl] -6,7 - difluoro-3 ,4 - dihydro-1H-quinolin - 2 - one; (R, S) -6,7 - difluoro-1 - [3 - (4 - piperidin-1-propoxy) -2 - methyl-propyl] -3,4 - dihydro-1H-quinolin- -2 - One; 1 - [3 - (4 - piperidin-1-butyl -) propyl]-6 - fluoro-7 - methyl-3 ,4 - dihydro-1H-quinolin-2 - one; 6 - fluorine -7 - Methyl-1 - [3 - (4 - propoxy-piperidin-1 -) propyl] -3,4 - dihydro-1H-quinolin-2 - one; (R, S) -1 - [3 - (4 - piperidin-1-butyl) -2 - methyl-propyl]-6 - fluoro-7 - methyl-3 ,4 - dihydro-1H-quinoline morpholine -2 - One; (R, S) -6 - fluoro-7 - methyl-1 - [2 - methyl -3 - (4 - piperidin-1-propoxy) - propyl] -3,4 - dihydro- -1H-quinolin-2 - one; 1 - [3 - (4 - butyl - piperidin-1 -) propyl]-6 - fluoro-5 - methyl-3 ,4 - dihydro-1H- quinoline -2 - one; 6 - fluoro-5 - methyl-1 - [3 - (4 - propoxy-piperidin-1 -) propyl] -3,4 - dihydro-1H-quinolin-2 - Ketone; (R) -1 - [3 - (4 - piperidinyl-1-butyl) -2 - methyl-propyl] -3,4 - dihydro-1H-quinolin-2 - one; (R) -1 - [2 - methyl-3 - (4 - propoxy-piperidin-1 -) propyl] -3,4 - dihydro-1H-quinolin-2 - one; (R) -1 - [3 - (4 - butylene-1 piperidinyl) -2 - methyl-propyl] -3,4 - dihydro-1H-quinolin-2 - one; (R) -1 - [3 - (3 - butyl-8 - aza-bicyclo [3.2.1] octyl -8) -2 - methyl-propyl] -3,4 - dihydro-1H-quinolin- -2 - One; (R) -1 - [2 - methyl-3 - (3 - pentyl-8 - aza-bicyclo [3.2.1] octyl -60 -) propyl] -3,4 - hydrogen -1H-quinolin-2 - one; 1 - [3 - (4 - butyl-piperidin-1 -) propyl]-1H-quinolin-2 - one; 1 - [3 - (4 - propoxy Piperidin-1 -) propyl]-1H-quinolin-2 - one; 1 - [3 - (4 - butyl-piperidin-1 -) propyl]-6 - fluoro-1H- Quinolin-2 - one; 1 - [3 - (4 - butyl-piperidin-1 -) propyl] -6 - methyl-1H-quinolin-2 - one; 1 - [3 - (4 - Ding Piperidin-1 -) propyl]-7 - fluoro-1H-quinolin-2 - one; 1 - [3 - (4 - butyl-piperidin-1 -) propyl] -6 - methyl Oxy-1H-quinolin-2 - one; 1 - [3 - (4 - butyl-piperidin-1 -) propyl] -6 - chloro-1H-quinolin-2 - one; 1 - [3 - (4 - butyl-piperidin-1 -) propyl] -5 - methyl-1H-quinolin-2 - one; 1 - [3 - (4 - butyl - piperidinyl -1 -) Propyl]-7 - methyl-1H-quinolin-2 - one; (R) -1 - [3 - (4 - piperidin-1-butyl) -2 - methyl-C Yl]-1H-quinolin-2 - one; (R) -1 - [2 - methyl-3 - (4 - piperidin-1-propoxy) - propyl]-1H-quinolin-2 - One; 1 - [3 - (4 - piperidin-allyloxy-1 -) propyl]-1H-quinolin-2 - one; (R, S) -4 - [3 - (4 - butyl piperazine Piperidine-1) -2 - methyl-propyl] -6 - methyl-4H-benzo [1.4] oxazin-3 - one; (R, S) -4 - [2 - methyl-3 - ( 4 - Propoxy-piperidin-1 -) propyl] -6 - methyl-4H-benzo [1.4] oxazin-3 - one; (R, S) -4 - [3 - (4 - Aden Piperidine-1) -2 - methyl-propyl] -6 - methyl-4H-benzo [1.4] oxazin-3 - one; (R, S) -4 - [3 - (3 - D -8 - aza-bicyclo [3.2.1] octyl -8) -2 - methyl-propyl] -6 - methyl-4H-benzo [1.4] oxazin-3 - one; (R, S) -4 - [2 - methyl-3 - (3 - pentyl-8 - aza-bicyclo [3.2.1] octyl -60 -) propyl] -6 - methyl-4H-phenyl And [1.4] oxazin-3 - one; (R, S) -4 - [3 - (4 - piperidin-1-butyl) -2 - methyl-propyl]-6 - fluoro-4H-benzo [1.4] oxazin-3 - one; (R, S) -6 - fluoro-4 - [2 - methyl -3 - (4 - propoxy-piperidin-1 -) propyl]-4H-phenyl and [1.4] oxazin-3 - one; (R, S) -4 - [3 - (4 - butylene-1 piperidinyl) -2 - methyl-propyl]-6 - fluoro-4H-benzo [1.4] oxazin-3 - one; (R, S) -4 - [3 - (3 - butyl-8 - aza-bicyclo [3.2.1] octyl -8) -2 - methyl-propyl Yl] -6 - fluoro-4H-benzo [1.4] oxazin-3 - one; (R, S) -6 - fluoro-4 - [2 - methyl -3 - (3 - pentyl-8 - N mixed pairs Ring [3.2.1] octyl -60 -) propyl]-4H-benzo [1.4] oxazin-3 - one; (R, S) -4 - [3 - (4 - piperidinyl butyl -1) -2 - Methyl-propyl]-7 - fluoro-4H-benzo [1.4] oxazin-3 - one; (R, S) -7 - fluoro-4 - [2 - methyl -3 - (4 - C Piperidin-oxy-1 -) propyl]-4H-benzo [1.4] oxazin-3 - one; (R, S) -4 - [3 - (4 - piperidinyl butylene -1 -) -2 - Methyl-propyl]-7 - fluoro-4H-benzo [1.4] oxazin-3 - one; (R, S) -4 - [3 - (3 - butyl-8 - aza Bicyclo [3.2.1] octyl -8) -2 - methyl-propyl]-7 - fluoro-4H-benzo [1.4] oxazin-3 - one; (R, S) -7 - fluoro- -4 - [2 - methyl - 3 - (3 - pentyl-8 - aza-bicyclo [3.2.1] octyl -60 -) propyl]-4H-benzo [1.4] oxazine 3 - one; (R, S) -3 - [3 - (4 - piperidin-1-butyl) -2 - methyl-propyl]-3H-benzothiazol-2 - one; (R, S) -4 - [2 - methyl-3 - (4 - propoxy-piperidin-1 -) propyl]-3H-benzothiazol-2 - one; (R, S) -4 - [3 - (4 - butylene-1 piperidinyl) -2 - methyl-propyl]-3H-benzothiazol-2 - one; (R, S) -3 - [3 - (3 - butyl-8 - aza-bicyclo [3.2.1] octyl -8) -2 - methyl-propyl]-3H-benzothiazol-2 - Ketone; (R, S) -3 - [2 - methyl-3 - (3 - pentyl-8 - aza-bicyclo [3.2.1] octyl -60 -) propyl]-3H-benzothiazol Oxazol-2 - one; (R, S) -4 - [3 - (4 - piperidin-1-butyl) -2 - methyl-propyl]-4H-benzo [1,4] oxazin-3- - Ketone; (R, S) -4 - [2 - methyl-3 - (4 - propoxy-piperidin-1 -) propyl]-4H-benzo [1,4] oxazin-3 - one ; (R, S) -4 - [3 - (4 - butylene-1 piperidinyl) -2 - methyl-propyl]-4H-benzo [1,4] oxazin-3 - one; (R, S) -4 - [3 - (3 - butyl-8 - aza-bicyclo [3.2.1] octyl -8) -2 - methyl-propyl]-4H-benzo [1,4] evil -3 - one; (R, S) -4 - [2 - methyl-3 - (3 - pentyl-8 - aza-bicyclo [3.2.1] octyl -60 -) propyl]-4H- benzene And [1,4] oxazin-3 - one; (R, S) -4 - [3 - (4 - piperidin-1-butyl) -2 - methyl-propyl]-4H-benzo [1 , 4] Thiazine-3 - one; (R, S) -1 - [2 - methyl-3 - (4 - propoxy-piperidin-1 -) propyl]-4H-benzo [1,4] thiazole triazine 3 - one; (R, S) -4 - [3 - (4 - butylene-1 piperidinyl) -2 - methyl-propyl]-4H-benzo [1,4] thiazine-3 - ketone; (R, S) -4 - [3 - (3 - butyl-8 - aza-bicyclo [3.2.1] octyl -8) -2 - methyl-propyl]-4H-benzo [1,4] thiophene -3 - one; (R, S) -4 - [2 - methyl-3 - (3 - pentyl-8 - aza-bicyclo [3.2.1] octyl -60 -) propyl]-4H- benzene And [1,4] thiazine-3 - one; (R, S) -1 - [3 - (4 - piperidin-1-butyl) -2 - methyl-propyl] -3,4 - dihydro- -1H- Quinolin-2 - one; (R, S) -1 - [2 - methyl-3 - (4 - propoxy-piperidin-1 -) propyl] -3,4 - dihydro-1H-quinoline morpholine -2 - One; (R, S) -1 - [3 - (4 - butylene piperidin-1-yl) -2 - methyl-propyl] -3,4 - dihydro-1H-quinolin-2 - ketone; (R, S) -1 - [3 - (3 - butyl-8 - aza-bicyclo [3.2.1] octyl -8) -2 - methyl-propyl] -3,4 - dihydro-1H- quinoline -2 - one; (R, S) -1 - [2 - methyl-3 - (3 - pentyl-8 - aza-bicyclo [3.2.1] octyl -60 -) propyl] -3, 4 - two Hydrogen-1H-quinolin-2 - one; (R, S) -4 - [3 - (4 - piperidinyl-1-butyl) -2 - methyl-propyl] -6 - methoxy-4H- Benzo [1,4] oxazin-3 - one; (R, S) -4 - [2 - methyl-3 - (4 - piperidin-1-propoxy)-6 - methoxy] - 4H- Benzo [1,4] oxazin-3 - one; (R, S) -4 - [3 - (4 - butylene-1 piperidinyl) -2 - methyl-propyl] -6 - methoxy- -4H-benzo [1,4] oxazin-3 - one; (R, S) -4 - [3 - (3 - butyl-8 - aza-bicyclo [3.2.1] octyl -8) - 2 - A Yl-propyl] -6 - methoxy-4H-benzo [1,4] oxazin-3 - one; (R, S) -1 - [2 - methyl-3 - (3 - pentyl-8 - Nitrogen Azabicyclo [3.2.1] octyl -60 -) propyl] -6 - methoxy-4H-benzo [1,4] oxazin-3 - one; (R, S) -4 - [3 - (4 - piperidin-1-butyl) -2 - methyl-propyl] -6,7 - difluoro-4H-benzo [1,4] oxazin - 3 - one; (R, S) -6,7 - difluoro-4 - [2 - methyl -3 - (3 - pentyl-8 - aza-bicyclo [3.2.1] octyl -60 -) propyl]-4H - Benzene And [1,4] oxazin-3 - one; (R, S) -4 - [3 - (3 - butoxy-8 - aza-bicyclo [3.2.1] octyl -8) -2 - methyl base Propyl]-6 - fluoro-4H-benzo [1,4] oxazin-3 - one; (R, S) -6 - fluoro-4 - {3 - [3 - (2 - methoxyethyl ) -8 - Azabicyclo [3.2.1] octyl -8 -] -2 - methyl-propyl}-4H-benzo [1,4] oxazin-3 - one; (R, S) -4 - [3 - (3 - butyl-azetidin) -2 - methyl-propyl]-6 - fluoro-4H-benzo [1,4] oxazin-3- - Ketone; (R, S) -6 - fluoro-4 - [2 - methyl -3 - (3 - propoxy-azetidin -) propyl]-4H-benzo [1,4] evil -3 - one; (R, S) -4 - [3 - (3 - butyl-azetidin) -2 - methoxy-propyl]-6 - fluoro-4H-benzo [1,4] oxazin-3 - one; 4 - [3 - (4 - butyl-3 - droperidol-1) -2 - methyl-propyl]-6 - fluoro-4H-benzo [ 1,4] Oxazin-3 - one. ...

[0106] chemical compound of the present invention has the ability that improves cholinergic receptor activity or activation cholinoceptor.Cholinergic receptor activity comprises active or any other the activity of signal, and it is directly or indirectly with the cholinergic signal or activate relevant.Cholinoceptor comprises muscarinic receptor, especially the M of muscarinic receptor ₁Or M ₄Hypotype.Muscarinic receptor for example can be in central nervous system, peripheral nervous system, gastronintestinal system, heart, endocrine gland or lung.Muscarinic receptor can be polytype, comprises truncate, cholinoceptor variation or modification.

[0107] also provide test kit, the directions for use that it contains chemical compound of the present invention and is used to implement the inventive method, the method for example is to improve cholinergic receptor activity or activation cholinoceptor.

[0108] system that contains cholinoceptor for example can be the experimenter, as mammal, inhuman primate or people.This system also can be in the body or the experiment in vitro model, as can expressing the cell culture model system of cholinoceptor, and contains cholinoceptor and not celliferous extract or purified receptor.The non-limitative example of this system is the tissue culture cells of expressed receptor, or its extract or lysate.

[0109] in the inventive method used cell comprise can be by cholinoceptor such as M ₁(for example the neuronal cell of some type is the natural M of expression for muscarinic receptor or the endogenous expression by receptor ₁Receptor) or with exogenous gene introduce any cell that cell (for example by using the plasmid transfection cell that contains acceptor gene) mediates the signal conduction.Because the cell of life form such as low lacks the suitable signal transduction pathway that is used for this purpose usually, so this cell mammalian cell (or other eukaryotic cell, as insect cell or xenopus (Xenopus) oocyte) normally.The concrete unrestricted example that is fit to cell comprises: the mice fibroblast is NIH 3T3 (ATCC CRL1658), by improve growth its can with the M of transfection ₁Receptor response; RAT 1 cell (Pace etc., Proc.Natl.Acad.Sci.USA 88:7031-35 (1991)); Pituicyte (Vallar etc., Nature330:556-58 (1987)).Other mammalian cell that is suitable for includes but not limited to HEK 293 cells, Chinese hamster ovary celI and COS cell.

[0110] chemical compound of the present invention also has the ability that reduces intraocular pressure, therefore can be used for treating the disease relevant with intraocular pressure, as glaucoma.Glaucoma is a kind of disease, wherein observes unusually in the loop control mechanism of the water sample liquid of filling cup, promptly forms the space between cornea and camera lens.This causes that the volume of water sample liquid increases and intraocular pressure increases, therefore because the compressing and the contraction of optic nerve mastoid process can cause visual field defectiveness, in addition blind.

[0111] thus, the present invention also provides the method for treatment mammal such as people's disease, and wherein the activity of cholinoceptor is regulated relevant with the useful reaction of physiology in the described mammiferous described disease.In one embodiment, method comprises the compound administration with the general formula I as defined above of effective dose, to obtain the useful reaction of physiology.Usually cholinoceptor is a muscarinic receptor, more generally cholinoceptor muscarinic M ₁-receptor subtype.Selectively, cholinoceptor is muscarinic M ₄-receptor subtype.

[0112] the present invention also provides treatment or prevention or alleviates method with mammal such as people's not normal relevant symptom.In one embodiment, method comprises the compound administration with the general formula I of effective dose, and is described not normal relevant with muscarinic receptor, for example with M ₁The muscarinic receptor hypotype is relevant, with treatment or prevention or alleviate one or more and not normal relevant symptom.

[0113] the common and muscarinic M of the useful reaction of physiology ₁-receptor subtype is with respect to muscarinic M ₂-or M ₃The selectivity of-receptor subtype is regulated relevant.In one embodiment, the chemical compound in the inventive method is a muscarinic agonist.

[0114] disease of compounds for treating of the present invention or not normal normally Mental Subnormality, and the useful reaction of physiology is because to M ₁Agonism, M ₁And M ₄Agonism, M ₁Agonism and D ₂Antagonism or M ₁And M ₄Agonism and D ₂The adjusting of antagonism.

[0115] another related aspect of the present invention relates to the method that improves cholinergic receptor activity.In one embodiment, method comprises that the system that makes cholinoceptor or contain cholinoceptor contacts with at least a chemical compound as defined above of effective dose to improve the activity of cholinoceptor.

Can determine by discussed above that [0116] chemical compound of the present invention is at least in part as medicament.Thereby the invention provides compositions, it contains i) one or more chemical compounds of general formula I as defined above; And ii) at least a pharmaceutically acceptable excipient or carrier.Owing to the present invention relates to the purposes of the chemical compound of general formula I as defined above, so the present invention's pharmaceutical composition of chemical compound, its pharmaceutically acceptable salt, its stereoisomer of general formula I also being provided or containing any above-mentioned substance is used for the treatment of purposes in disease relevant with cholinoceptor or its part or the not normal medicine in preparation.

[0117] thus the present invention partly relates to and treats or prevent or alleviate one or more and the method for mammal such as people's not normal relevant symptom.In one embodiment, method comprises the compound administration with the general formula I of effective dose, and is described not normal relevant with muscarinic receptor, for example with M ₁The muscarinic receptor hypotype is relevant, with prevention or alleviate one or more symptoms.Be selected from following those not normal comprising: cognitive impairment, forgetful, confusion, memory loss, attention disappearance, the blindness, depression, pain, sleep disordered, psychosis and intraocular pressure increase.Be selected from following those not normal also comprising: neurodegenerative disease, Alzheimer disease, Parkinson's disease, schizophrenia, Huntington chorea, family ataxia, Ji Liedela tell auspicious syndrome, Down's syndrome, Niemann-Pick disease, dementia, clinical melancholia, with age cognitive decline, attention deficiency, sudden infant death syndrome and glaucoma relatively.Therefore, the invention still further relates to the chemical compound of general formula I, its pharmaceutically acceptable salt, its stereoisomer or the pharmaceutical composition that contains any above-mentioned substance are used for being selected from the purposes of following those diseases or not normal medicine in preparation: Alzheimer disease, Parkinson's disease, schizophrenia, Huntington chorea, family ataxia, Ji Liedela tells auspicious syndrome, Down's syndrome, Niemann-Pick disease, dull-witted, clinical melancholia, with age cognitive decline relatively, cognitive impairment, forgetful, confusion, lose memory, note disappearance, the blindness, depressed, pain, sleep disordered, psychosis, sudden infant death syndrome, intraocular pressure increases and glaucoma.

[0118] chemical compound of the present invention can use separately with the suitable dosage of determining by routine test, thereby to muscarinic receptor, especially muscarinic M ₁Or M ₄Receptor subtype obtains best pharmacological action, minimizes any potential toxicity or other unwanted effect simultaneously.In addition, the common administration or the successive administration that can improve other medicament of compound effects needs in some cases.

[0119] The compounds of this invention can utilize the recombinant receptor hypotype to confirm by many different detection methods to the pharmacological characteristics of specific muscarinic receptor hypotype and selectivity, as available people's receptor, and Chang Gui second message,second messenger or for example in conjunction with detecting.A kind of function detecting system especially easily is at United States Patent (USP) the 5th, 707, disclosed acceptor selection and augmentation detection system in No. 798, this patent has been described a kind of method of utilizing cell to screen bioactive compound in the amplification ability that exists under the situation of receptors ligand, and cell wherein is by for example receptor dna transfection of the different muscarine hypotypes of codified.The amplification of cell is that the increase level according to the labelling of cellular expression detects.

[0120] below by embodiment openly the present invention in more detail.

Embodiment

Embodiment 1

Synthetic chemistry

The LC-MS universaling analysis method

Method 1:

[0121] use HP1100 LC/MSD instrument to obtain spectrum.Use has the equipment at double pump, automatic sampler, column oven, diode array detector, plating splash ionizing interface.Use has the anti-phase post (C18 Luna 3 μ, 75 * 4.6mm ID) of guard column cartridge type system.Mobile phase is the MeCN/8mM ammonium acetate solution.Use 15 minutes gradient programs, initial 70%MeCN, 95%MeCN after 12 minutes, 70%MeCN after 1 minute continues 2 minutes.Flow velocity is 0.6ml/min.

Method 2:

[0122] use Waters LC/ZMD instrument to obtain spectrum.Use has 600 gradient pumps, 2700 sample managing devices, 996 diode array detector, electroplates the equipment at splash ionizing interface.Use has the anti-phase post (C18 X-Terra 5 μ, 50 * 4.6mm ID) of guard column cartridge type system.Mobile phase is the MeCN/10mM ammonium acetate solution.Use 14 minutes gradient programs, initial 30%MeCN, 95%MeCN after 10 minutes continues 2 minutes, and 30%MeCN after 0.5 minute continues 4.5 minutes.Flow velocity is 1ml/min.

The general preparation method of LC-MS

Method 1:

[0123] being prepared property purification on the automatic purification system of Waters (600 pumps, 2700 sample managing devices, 996 PDA detectors, ZMD mass spectrograph).

[0124] post of Shi Yonging is YMC C18 J ' sphere ODS H80.Buffer A is the 0.15%TFA aqueous solution, and buffer B is that the MeCN/ water of 0.15%TFA is 95/5 solution.This post turns round with 17ml/min.At first load 30% buffer B 2.5min, then use the buffer B 8.5min separating compound of 30-100% gradient.When a post operation, come another post of balance with the twin columns that are equipped with two pumps.

Method 2:

[0125] being prepared property purification on Waters Delta 4000 preparation systems, 2487 pairs of absorptance detectors of Water, Waters fraction collector II.Used post is Luna 15 μ m C18,250 * 21.2mm.Mobile phase H below using ₂O/MeCN ammonium acetate buffer (25nM) or H ₂O/MeCN TFA buffer (25nM).

[0126] (microwave irradiation Sweden) heats for Personal Chemistry AB, Uppsala, and it can produce successive radiation at 2.45GHz with having Smith Creator one-mode cavity.Handle the reaction of carrying out microwave-assisted in the bottle at the Smith with cover that the magnetic puddler is installed.For guaranteeing enough irradiation absorption, liquid sample volume is 〉=0.5mL.

[0127] (6ml) post carries out cation exchange CC for mega BE-SCX, 1g to use Varian BOND ELUT.After being added to chemical compound on the post, at first use MeOH (2 times of column volumes) to wash pillar, use the NH of 2 times of column volumes then ₄OH (H ₂25% NH among the O ₃)/MeOH mixture (1: 9) eluting pillar obtains required compound.

(R, S)-1-(4-butyl piperidine base-1)-3-chlorine propan-2-ol (101IS93-1)

[0128] in the bottle of 4mL, add the 4-butyl piperidine (0.29g, 2.0mmol) and chloropropylene oxide (0.190g 2.1mmol), and at room temperature shakes 4h.With flash chromatography (SiO ₂CH ₂Cl ₂/ acetone/MeOH 85/10/5) the thickness grease of purification generation obtains buttery title compound (0.31g, 64%). ¹H?NMR(CDCl ₃)δ3.95-3.85(m，1H)，3.60-3.48(m，1H)，2.97-2.88(m，1H)，2.82-2.72(m，1H)，2.46-2.35(m，1H)，2.30-2.20(m，1H)，1.98-1.88(m，1H)，1.70-1.58(m，2H)，1.35-1.08(m，9H)，0.88(t，J＝6.8Hz，3H)； ¹³CNMR(CDCl ₃)δ66.7，61.5，55.9，53.1，47.4，36.4，35.8，32.9，32.6，29.2，23.1，14.3。

(R, S)-4-butyl-1-(3-chloro-2-fluoropropyl) piperidines (101IS93-2)

[0129] DAST (1.9mmol, 230 μ L) is added to dropwise 1-(4-butyl piperidine base-1)-(0.31g 1.28mmol) is dissolved in CH to 3-chlorine propan-2-ol (101IS93) ₂Cl ₂(5mL) in the solution that is become.Behind the 2h, add entry (5mL) quencher reaction, use CH ₂Cl ₂(2 * 15mL) extracted organic phase merge organic facies, dry (Na ₂SO ₄), filter concentrating under reduced pressure, residue flash chromatography (SiO ₂Heptane/EtOAc60: 40) purification obtains buttery title compound (0.025g, 9%); ¹H NMR (CDCl ₃) δ 4.79 (dm, J=48Hz, 1H), 3.78-3.60 (m, 2H), 2.92-2.83 (m, 2H), 2.72-2.56 (m, 2H), 2.15-2.00 (m, 2H), 1.69-1.58 (m, 2H), 1.35-1.16 (m, 9H), 0.88 (t, J=6.8Hz); ¹³C NMR (CDCl ₃) δ 91.1 (d, J=111Hz), 59.9 (d, J=22Hz), 55.2,54.9,44.9 (d, J=25Hz), 36.4,35.6,32.7,32.6,29.2,23.1,14.3.

Universal method 1 (GP1)

[0130] in flask or bottle, adds the 2-amino-phenol (1.0 equivalent) be dissolved among the DMF (0.1g/mL), add 2-chloracetyl chloride (1.1 equivalent) again.Reaction was at room temperature stirred 12-20 hour, added K ₂CO ₃(2.1 equivalent).Reacted at room temperature restir 12-20 hour, be evaporated to then dried, in water-soluble (10mL), with EtOAc (3 * 20mL) extraction.Merge organic facies, concentrate crude product, it can directly use or with CC (heptane: EtOAc) purification.

4H-pyrido [4,3-b] [1,41 thiazine-3-ketone (81MF939a)

[0131] according to GP1 mixing 3-amino-4-sulfo-pyridine (0.10g, 0.79mmol), the 2-chloracetyl chloride (0.098g, 0.87mmol) and K ₂CO ₃(0.23g, 1.66mmol), the crude product (81MF939a) that obtains title compound (0.087g).

8-fluoro-4H-benzo [1,4] oxazine-3-ketone (95MF45)

[0132] according to GP1 mixing 2-amino-6-fluorophenol (95MF2085) (0.256g, 2.0mmol), the 2-chloracetyl chloride (0.25g, 2.2mmol) and K ₂CO ₃(0.583g, 4.2mmol), the crude product (95MF45) that obtains title compound (0.29g).

7-fluoro-4H-benzo [1,4] oxazine-3-ketone (111MF12)

[0133] according to GP1 mixing 2-amino-5-fluorophenol (111MF10) (10.3g, 81mmol), the 2-chloracetyl chloride (10.1g, 89mmol) and K ₂CO ₃(23.5g, 170mmol).CC (SiO ₂Heptane/EtOAc 4: 1-4), obtain title compound (111MF12) (12.6g, 93%); ¹H NMR (DMSO) δ 10.68 (s, 1H), 6.83-6.91 (m, 2H), 6.75-6.80 (m, 1H), 4.57 (s, 2H); ¹³CNMR (DMSO) δ 164.2,157.8 (d, J=238.6Hz), 144.0 (d, J=12.4Hz), 123.9 (d, J=2.7Hz), 116.3 (d, J=9.6Hz), 108.6 (d, J=22.7Hz), 104.0 (d, J=26.5Hz), 66.7.

7,8-two fluoro-4H-benzo [1,4] oxazine-3-ketone (81MF2082A)

[0134] according to GP1 mixing 6-amino-2,3-difluorophenol (81KK30a) (0.113g, 0.78mmol), the 2-chloracetyl chloride (0.10g, 0.89mmol) and K ₂CO ₃(0.226g, 1.6mmol), the crude product (81MF2082A) that obtains title compound (0.12g).

6-bromo-8-fluoro-4H-benzo [1,4] oxazine-3-ketone (95MF44)

[0135] according to GP1 mixing 2-amino-4-bromo-6-fluorophenol (95MF2084) (0.078g, 0.38mmol), the 2-chloracetyl chloride (0.048g, 0.42mmol) and K ₂CO ₃(0.11g, 0.79mmol), the crude product (95MF44) that obtains title compound (0.091g).

8-isopropyl-4H-benzo [1,4] oxazine-3-ketone (95MF83)

[0136] according to GP1 mixing crude product 2-amino-6-isopropyl-phenol (95MF80 (2240) (and 0.16g, 1.1mmol), the 2-chloracetyl chloride (0.14g, 1.2mmol) and K ₂CO ₃(0.32g, 2.3mmol), the crude product (95MF83) that obtains title compound (0.115g).

6,8-two chloro-7-methyl-4H-benzo [1,4] oxazine-3-ketone (81MF2225)

[0137] according to GP1 mixing 6-amino-2.4-two chloro-3-metyl phenol (1.9g, 10mmol), the 2-chloracetyl chloride (1.2g, 11mmol) and K ₂CO ₃(3.0g, 22mmol), the crude product (80MF2225) that obtains title compound (2.33g).

6,8-two chloro-7-ethyls-4H-benzo [1,4] oxazine-3-ketone (95MF46)

[0138] according to GP1 mixing 6-amino-2.4-two chloro-3-ethyl-phenols (95MF2226) (0.293g, 1.5mmol), the 2-chloracetyl chloride (0.19g, 1.7mmol) and K ₂CO ₃(0.44g, 3.2mmol), the crude product (95MF46) that obtains title compound (0.34g).

7-fluoro-6-methyl-3,4-dihydro-1H-quinoline-2-one-(97KK40)

[0139] 40 ℃ of stirrings be dissolved in 3-fluoro-4-monomethylaniline. among the MeCN (10mL) (1.247g, 9.96mmol), the 3-chlorpromazine chloride (1.269g, 9.99mmol) and K ₂CO ₃(1.450g 10.5mmol) reaches 3h.With 4M HCl quencher reactant mixture, product extracts into CH ₂Cl ₂Merge organic layer, use Na ₂SO ₄Drying is filtered, and concentrates.(1.168g) is heated to 145 ℃ with residue, adds AlCl in the 30min in batches ₃(3.538g, 26.5mmol).Reaction mixture stirs adding 4M HCl down then, and CH is advanced in extraction then ₂Cl ₂Merge organic layer, use Na ₂SO ₄Drying is filtered, and concentrates.Residue is with quick CC (SiO ₂CH ₂Cl ₂/ MeOH 40: 1) purification obtains title compound (97KK40) (0.201g, gross production rate 11%). ¹H?NMR(CDCl ₃)δ8.15(brs，1H)，6.94(d，J＝7.8Hz，1H)，6.47(d，J＝10.0Hz，1H)，2.91-2.87(m，2H)，2.62-2.60(m，2H)，2.19(d，J＝1.8Hz，CH ₃)。

6-fluoro-1H-quinoline-2-one-(97KK38)

[0140] (0.38g 1.7mmol) is added to 6-fluoro-3, and (0.18g 1.1mmol) is dissolved in the solution of dioxane (25mL) 4-dihydro-1H-quinoline-2-one-, the solution backflow 16h that obtains with DDQ.Enriched mixture adds saturated Na ₂CO ₃(25mL) aqueous solution is used organic mixture (MeOH: CH then ₂Cl ₂1: 10,3 * 50mL) extractions.Merge organic facies, use Na ₂SO ₄Drying is filtered, and concentrating under reduced pressure is with quick CC (SiO ₂CH ₂Cl ₂/ MeOH 20: 1) purification obtains title compound (0.056g, 31%). ¹H?NMR(DMSO-D ₆)δ11.8(brs，1H)，7.85(d，J＝9.4Hz)，7.50(dd，J＝2.8，9.2Hz)，7.43-7.37(m，1H)，7.37-7.25(m，1H)，6.54(d，J＝9.4Hz)。

7-fluoro-1H-quinoline-2-one-(97KK34)

[0141] (0.42g 1.9mmol) is added to 7-fluoro-3, and (0.20g 1.2mmol) is dissolved in the solution of dioxane (25mL) 4-dihydro-1H-quinoline-2-one-, the mixture that the obtains 16h that refluxes in argon with DDQ.The concentrating under reduced pressure mixture adds saturated Na ₂CO ₃(25mL) aqueous solution, and with organic mixture (MeOH: CH ₂Cl ₂1: 10,3 * 50mL) extractions.Merge organic facies, use Na ₂SO ₄Drying is filtered, and concentrating under reduced pressure is with compound quick LC (SiO ₂CH ₂Cl ₂/ MeOH 10: 1) purification obtains title compound (0.037g, 18%). ¹H?NMR(DMSO-D ₆)δ11.8(s，1H)，7.88(d，J＝9.6Hz，1H)，7.74-7.65(m，1H)，7.05-6.95(m，2H)，6.43(d，J＝9.6Hz)； ¹³CNMR(CDMSO-D ₆)δ163.0(d，J＝247Hz)，161.9，140.4(d，J＝13Hz)，130.4(d，J＝11Hz)，120.9，116.1，109.8(d，J＝23)，101.0(d，J＝25Hz)。

6-fluoro-7-methyl-3,4-dihydro-1H-quinoline-2-one-(10LH75-1) and 6-fluoro-5-methyl-3,4-dihydro -1H-quinoline-2-one-(107LH75-2)

[0142] with 3-chloro-N-(4-fluoro-3-methyl-phenyl)-propionic acid amide. (3.8g, 30mmol), the 3-chlorpromazine chloride (2.9mL, 30mmol) and K ₂CO ₃(5.0g 36mmol) is added to CH ₃Among the CN (50mL), mixture at room temperature stirs 44h.Subsequently, reaction is with EtOAc (50mL) dilution, and water (20mL), HCl (20mL, 4N) and saline (20mL) wash.Use Na ₂SO ₄Dry organic facies is filtered concentrating under reduced pressure.(5.9g) is heated to 135 ℃ with residue, adds AlCl in the 30min in batches ₃(11g 82mmol), is chilled to reaction 50 ℃ then, adds HCl (4N 20mL), and the mixture that obtains stirs 15min.With EtOAc (50mL) extraction mixture, water (20mL) washing organic facies.Dry (Na ₂SO ₄) organic facies that obtains, filtering, concentrating under reduced pressure with preparation property HPLC purification, obtains 6-fluoro-7-methyl-3,4-dihydro-1H-quinoline-2-one-(0.76g, 14%) and 6-fluoro-5-methyl-3,4-dihydro-1H-quinoline-2-one-(0.190g, 4%).6-fluoro-7-methyl-3,4-dihydro-1H-quinoline-2-one-(107LH75-1): ¹HNMR (CDCl ₃) δ 8.86 (brs, 8.86,1H), 6.81 (d, J=9.2Hz, 1H), 6.62 (d, J=6.8Hz, 1H), 2.91 (brt, J=7.6Hz, 3H), 2.94-2.87 (m, 2H), 2.20 (d, J=2.0Hz).6-fluoro-5-methyl-3,4-dihydro-1H-quinoline-2-one-(107LH75-2): ¹H NMR (CDCl ₃) δ 8.78 (brs, 1H), 6.85 (t, J=8.8Hz, 1H), 6.62 (dd, J=4.5,8.8Hz, 1H), 2.92 (brt, J=7.6Hz, 2H), 2.64-2.58 (m, 2H), 2.20 (d, J=2.4Hz, 3H).

(R)-4-(3-hydroxy-2-methyl propyl group-4H-benzo [1,4] oxazine-3-ketone (108LM40-37)

[0143] in the 25mL flask, adds the 4H-benzo [1 that is dissolved among the MeCN (10mL), 4] oxazine-3-ketone (0.100g, 0.670mmol), (S)-3-bromo-2-methylpropanol (0.103g, 0.670mmol) and cesium carbonate (0.208g, 0.670mmol), and under 40 ℃, stirred 2 days.Reactant mixture water (5mL) quencher, (2 * 10mL) extract product with EtOAc.Merge organic layer, dry (Na ₂SO ₄), evaporate, obtain the crude product (0.219g) of title compound (108LM40-37).

Universal method 2 (GP2)

[0144] add corresponding heterocyclic compound (1.1 equivalent), (R)-(3-bromo-2-methyl-propoxyl group)-tert-butyl group-dimethylsilane (95MF94) (1 equivalent) and the cesium carbonate (2.5 equivalent) that is dissolved among the DMF (20mL) in doing the 50mL flask, 55 ℃ are stirred 20h down.Reactant mixture water (10mL) quencher, (3 * 20mL) extract product with EtOEt.Merge organic layer, use the salt water washing, dry (Na ₂SO ₄), evaporation is with quick CC (SiO ₂EtOAc/ heptane 1: 10) purification.

(S)-4-[3-(tert-butyl group dimethyl-silicon alcoxyl base)-2-methyl-propyl]-4H-benzo [1,4] oxazine-3-ketone (108LM24-21)

[0145] according to GP2 make the 4H-benzo that is dissolved among the DMF (20mL) [1,4] oxazine-3-ketone (and 2.47g, 16.5mmol), (R)-(3-bromo-2-methyl-propoxyl group)-tert-butyl group dimethylsilane (95MF94) (4.01g, 15.0mmol) and Cs ₂CO ₃(12.2g, 37.6mmol) reaction obtains title compound (108LM24-21) (3.92g, 78%). ¹H?NMR(CDCl ₃)δ7.15-7.11(m，1H)，6.99-6.91(m，3H)，4.60-4.50(m，2H)，3.98(dd，J＝8.3Hz，J＝12.4Hz，1H)，3.81(dd，J＝5.5Hz，J＝12.4Hz，1H)，3.51(dd，J＝4.1Hz，J＝9.7Hz，1H)，3.40(dd，J＝6.9Hz，J＝9.7Hz，1H)，2.12-2.02(m，1H)，0.90-0.82(m，12H)，0.02(s，6H)。

(S)-4-[3-(tert-butyl group dimethyl-silicon alcoxyl base)-2-methyl-propyl]-4H-benzo [1,4] thiazine-3-ketone (108LM25-22)

[0146] makes the 4H-benzo [1 that is dissolved among the DMF (20mL) according to GP2,4] thiazine-3-ketone (2.75g, 16.7mmol), (R)-(3-bromo-2-methyl propoxyl group)-tert-butyl group dimethylsilane (95MF94) (4.04g, 15.1mmol) and cesium carbonate (12.3g, 37.9mmol) reaction, obtain title compound (108LM25-22) (3.74g, 70%). ¹H?NMR(CDCl ₃)δ7.35(d，J＝7.6Hz，1H)，7.28-7.18(m，2H)，6.99(t，J＝7.6Hz，1H)，4.13(dd，J＝8.9Hz，J＝13.3Hz，1H)，3.95(dd，J＝5.9Hz，J＝13.3Hz，1H)，3.52-3.40(m，2H)，3.37(s，CH ₂)，1.96-2.07(m，1H)，0.92-0.83(m，12H)，0.02(s，6H)。

Universal method 3 (GP3)

[0147] in the 50mL flask, adds corresponding heterocyclic compound (1 equivalent) and the tetrabutyl ammonium fluoride (TBAF) (1.3 equivalent) that is dissolved among the THF (30mL), and at room temperature stir 20h.Reactant mixture is condensed into slurry, and is dissolved among the EtOAc (30mL).(2 * 20mL) wash mixture with saline.Merge organic layer, dry (Na ₂SO ₄), evaporation is with quick CC (SiO ₂EtOAc/ heptane 7: 3) purification.

(S)-4-(3-hydroxy-2-methyl propyl group)-4H-benzo [1,4] oxazine-3-ketone (108LM26-23)

[0148] make chemical compound (S)-4-[3-(tert-butyl group dimethyl-silicon alcoxyl base)-2-methyl-propyl that is dissolved among the THF (30mL) according to GP3]-4H-benzo [1,4] oxazine-3-ketone (108LM24-21) (3.92g, 11.7mmol) and TBAF (4.78g, 15.2mmol) reaction, obtain title compound (108LM26-23) (2.52g, 98%). ¹H?NMR(CDCl ₃)δ7.05-6.95(m，4H)，4.63(s，CH ₂)，4.23(dd，J＝10.3Hz，J＝13.9Hz，1H)，3.56(dd，J＝4.8Hz，J＝13.9Hz，1H)，3.52-3.49(m，1H)，3.46-3.38(m，1H)，2.92-2.85(m，1H)，2.09-1.97(m，1H)，1.06(d，J＝7.3Hz，CH ₃)。

(S)-4-[3-(tert-butyl group dimethyl-silicon alcoxyl base)-2-methyl-propyl]-4H-benzo [1,4] thiazine-3-ketone

[0149] according to GP3 make the chemical compound (108LM25-22) that is dissolved among the THF (30mL) (3.69g, 10.5mmol) and TBAF (4.30g, 13.6mmol) reaction.With quick CC (SiO ₂EtOAc/ heptane 7: 3) purification obtains title compound (108LM34-31) (2.36g, 95%). ¹H?NMR(CDCl ₃)δ7.38(d，J＝7.9Hz，1H)，7.28-7.18(m，2H)，7.03(t，J＝7.0Hz，1H)，4.32(dd，J＝9.0Hz，J＝15.2Hz，1H)，3.70(dd，J＝5.5Hz，J＝15.2Hz，1H)，3.52(dd，Jn＝3.4Hz，J＝11.7Hz，1H)，3.34-3.42(m，3H)，2.82(bs，OH)，1.92-1.83(m，1H)，0.98(d，J＝6.9Hz，CH ₃)。

Universal method 4 (GP4)

[0150] adding is dissolved in CHCl in the 50mL flask ₃Corresponding heterocyclic compound (30mL) (1 equivalent), triphenylphosphine (2 equivalent) and imidazoles (2.5 equivalent).After all substance dissolves, stir adding iodine (3 equivalent) down.Continue to stir 20h under the room temperature.Reactant mixture washs with saturated aqueous sodium thiosulfate (30mL), dry (Na ₂SO ₄), evaporation is with quick CC (SiO ₂EtOAc/ heptane 3: 1) purification.

(S)-4-(3-iodo-2-methyl-propyl)-4H-benzo [1,4] oxazine-3-ketone (108LM27-24)

[0151] makes according to GP4 and be dissolved in CHCl ₃Chemical compound (30mL) (S)-4-(3-hydroxy-2-methyl propyl group)-4H-benzo [1,4] oxazine-3-ketone (108LM26-23) (2.52g, 11.4mmol), triphenylphosphine (6.12g, 23.3mmol), imidazoles (1.98g, 29.1mmol) and iodine (8.88g, 35.0mmol) reaction, obtain title compound (108LM27-24) (3.02g, 80%). ¹H?NMR(CDCl ₃)δ7.07-7.00(m，4H)，4.65-4.55(m，2H)，3.94(dd，J＝1.7Hz，J＝6.7Hz，CH ₂)，3.23-3.14(m，2H)，2.18-2.07(m，1H)，1.05(d，J＝6.1Hz，CH ₃)。

(R)-4-(3-iodo-2-methyl-propyl)-4H-benzo [1,4] oxazine-3-ketone (108LM46-43)

[0152] makes according to GP4 and be dissolved in CHCl ₃(R)-4-(30mL) (3-hydroxy-2-methyl propyl group)-4H-benzo [1,4] oxazine-3-ketone (108LM40-37) is crude product, triphenylphosphine (0.99g (1.040g), 3.77mmol), imidazoles (0.32g, 4.71mmol) and iodine (1.43g, 5.65mmol) react, obtain the crude product (0.312g) of title compound (108LM46-43).

(S)-4-(3-iodo-2-methyl-propyl)-4H-benzo [1,4] thiazine-3-ketone (108LM37-34)

[0153] makes according to GP4 and be dissolved in CHCl ₃Chemical compound (30mL) (S)-4-(3-hydroxy-2-methyl propyl group)-4H-benzo [1,4] thiazine-3-ketone (108LM34-31) (2.33g, 9.82mmol), triphenylphosphine (5.15g, 19.7mmol), imidazoles (1.67g, 24.6mmol) and iodine (7.48g, 29.5mmol) reaction, obtain title compound (108LM37-34) (2.57g, 75%). ¹H?NMR(CDCl ₃)δ7.37(d，J＝7.8Hz，1H)，7.24(t，J＝7.8Hz，1H)，7.16(d，J＝7.8Hz，1H)，7.02(t，J＝7.8Hz，1?H)，4.02(d，J＝6.8Hz，CH ₂)，3.37(s，CH ₂)，3.15-3.05(m，CH ₂)，1.95(m，1H)，0.97(d，J＝6.2Hz，CH ₃)。

Universal method 5 (GP5)

[0154] 4 or the bottle of 7mL in add and be dissolved in 4H-benzo [1,4] oxazine-3-ketone (1.0 equivalent), the Cs that 3mL does MeCN ₂CO ₃(1.5 equivalent) and 3-chloro-propyl iodide (1.1 equivalent), and at room temperature shake 66-72h.Use 10mL H ₂The O diluted reaction mixture, and use CH ₂Cl ₂Or EtOAc (3 * 30mL) extractions.Merge organic layer, use MgSO ₄Drying, or with the filtration of PTFF Whatman filter, concentrate.Residue is with the CC (purification of heptane/EtOAc), or be directly used in next step without being further purified.

6-bromo-4-(3-chloropropyl)-8-fluoro-4H-benzo [1,4] oxazine-3-ketone (95MF50 (2084))

[0155] according to GP5 mixing 6-bromo-8-fluoro-4H-benzo [1,4] oxazine-3-ketone (95MF44) (and 0.091g, 0.37mmol), Cs ₂CO ₃(0.180g, 0.55mmol) and 3-chloro-propyl iodide (0.083g, 0.41mmol).CC (SiO ₂Heptane/EtOAc 9: 1-4), obtain title compound (95MF50 (2084)) (0.086g, 72%). ¹H?NMR(CDCl ₃)δ7.02-6.96(m，1H)，6.85(d，J＝5.2Hz，1H)，4.65(s，2H)，4.04-4.11(m，2H)，3.62(t，J＝6.2Hz，2H)，2.10-2.18(m，2H)； ¹³C?NMR(CDCl ₃)δ163.8，151.7(d，J＝250.9Hz)，133.1(d，J＝14.6Hz)，131.5(d，J＝3.8Hz)，115.1(d，J＝21.5Hz)，114.2(d，J＝10.0Hz)，113.4(d，J＝3.4Hz)，67.6，42.2，39.5，30.0。

4-(3-chloropropyl)-8-fluoro-4H-benzo [1,4] oxazine-3-ketone (95MF51 (2085))

[0156] according to GP5 mixing 8-fluoro-4H-benzo [1,4] oxazine-3-ketone (95MF45) (and 0.290g, 1.74mmol), Cs ₂CO ₃(0.848g, 2.6mmol) and 3-chloro-propyl iodide (0.390g, 1.91mmol).CC (SiO ₂Heptane/EtOAc 9: 1-4), obtain title compound (95MF51 (2082)) (0.254g, 60%). ¹H?NMR(CDCl ₃)δ7.01-6.95(m，1H)，6.88-6.82(m，2H)，4.66(s，2H)，4.13-4.08(m，2H)，3.63(t，J＝6.0Hz，2H)，2.19-2-12(m，2H)； ¹³C?NMR(CDCl ₃)δ164.2，152.1(d，J＝246.8Hz)，133.9(d，J＝15.0Hz)，130.6(d，J＝3.1Hz)，122.6(d，J＝8.1Hz)，111.8(d，J＝18.4Hz)，110.1(d，J＝3.4Hz)，67.8，42.4，39.5，30.1。

6,8-two chloro-4-(3-chloropropyl)-7-ethyl-4H-benzo [1,4] oxazine-3-ketone ((95MF52 (2226))

[0157] mix 6 according to GP5, and 8-two chloro-7-ethyls-4H-benzo [1,4] oxazine-3-ketone (95MF46) (0.342g, 1.39mmol), Cs ₂CO ₃(0.678g, 2.08mmol) and 3-chloro-propyl iodide (0.313g, 1.52mmol).CC (SiO ₂Heptane/EtOAc 9: 1-4), obtain title compound (95MF52 (2226)) (0.301g, 67%). ¹H?NMR(CHCl ₃)δ7.01(s，1H)，4.68(s，2H)，4.06(t，J＝7.2Hz，2H)，3.62(t，J＝6.0Hz，2H)，2.91(q，J＝7.6Hz，2H)，2.10-2.18(m，2H)，1.16(t，J＝7.6Hz，3H)； ¹³C?NMR(CDCl ₃)δ163.8，140.6，135.8，127.9，127.7，123.6，113.8，67.9，42.2，39.3，30.0，24.7，12.7。

4-(3-chloropropyl)-8-isopropyl-4H-benzo [1,4] oxazine-3-ketone (95MF98)

[0158] according to GP5 mixing 8-isopropyl-4H-benzo [1,4] oxazine-3-ketone (95MF83) (and 0.115g, 0.60mmol), Cs ₂CO ₃(0.293g, 0.90mmol) and 3-chloro-propyl iodide (0.135g, 0.66mmol).CC (SiO ₂Heptane/EtOAc 9: 1-4), obtain title compound (95MF98) (0.112g, 70%). ¹H?NMR(CDCl ₃)δ7.03-6.95(m，2H)，6.93-6.90(m，1H)，4.57(s，2H)，4.09(m，2H)，3.62(t，J＝6.2Hz，2H)，3.33-3.25(m，1H)，2.20-2.13(m，2H)，1.22(d，J＝7.2Hz，6H)； ¹³C?NMR(CDCl ₃)δ164.9，142.8，137.8，128.5，122.8，121.4，112.5，67.7，42.5，39.3，30.3，27.2，22.7。

4-(3-chloropropyl)-6-fluoro-4H-benzo [1,4] oxazine-3-ketone (8173MF55b)

[0159] according to GP5 mixing 6-fluoro-4H-benzo [1,4] oxazine-3-ketone (8173MF55b) (and 0.090g, 0.54mmol), Cs ₂CO ₃(0.263g, 0.81mmol) and 3-chloro-propyl iodide (0.121g, 0.59mmol).CC (SiO ₂Heptane/EtOAc 10: 1-5), obtain title compound (8173MF55b) (0.102g, 78%). ¹H?NMR(CDCl ₃)δ6.95-6.91(m，1H)，6.82-6.78(m，1H)，6.72-6.67(m，1H)，4.57(s，1H)，4.05(t，J＝7.2Hz，2H)，3.62(t，J＝6.2Hz，2H)，2.19-2.11(m，2H)； ¹³C?NMR(CDCl ₃)δ164.6，158.6(d，J＝240.7Hz)，141.5(d，J＝2.3Hz)，129.6(d，J＝10.5Hz)，118.0(d，J＝9.3Hz)，110.0(d，J＝23.1Hz)，102.7(d，J＝28.8Hz)，67.8，42.3，39.3，30.0。

4-(3-chloropropyl)-7,8-two fluoro-4H-benzo [1,4] oxazine-3-ketone (81MF2082b)

[0160] mix 7 according to GP5, and 8-two fluoro-4H-benzo [1,4] oxazine-3-ketone (81MF2082a) (0.119g, 0.64mmol), Cs ₂CO ₃(0.314g, 0.96mmol) (0.144g 0.70mmol), obtains the crude product of title compound (0.156g) with 3-chloro-propyl iodide; ¹HNMR (CDCl ₃) δ 6.89-6.82 (m, 1H), 6.78-6.74 (m, 1H), 4.68 (s, 2H), 4.08 (t, J=7.2Hz, 2H), 3.62 (t, J=6.4Hz, 2H), 2.18-2.10 (m, 2H); ¹³C NMR (CDCl ₃) δ 163.5,147.7 (q, J=245.6Hz, J=10.4Hz), 141.0 (q, J=249.4Hz, J=15.7Hz), 135.5,126.2,109.9 (d, J=18.4Hz), 108.6 (q, J=7.6Hz, J=4.2Hz), 67.8,42.3,39.4,30.0.

4-(3-chloropropyl)-6-methoxyl group-4H-benzo [1,4] oxazine-3-ketone (81MF2249b)

[0161] according to GP5 mixing 6-methoxyl group-4H-benzo [1,4] oxazine-3-ketone (81MF2249a) (and 0.212g, 1.18mmol), Cs ₂CO ₃(0.578g, 1.77mmol) and 3-chloro-propyl iodide (0.265g, 1.3mmol).CC (SiO ₂Heptane/EtOAc 10: 1-2), obtain title compound (81MF2249b) (0.127g, 42%). ¹H?NMR(CDCl ₃)δ6.88(d，J＝8.8Hz，1H)，6.62(d，J＝2.8Hz，1H)，6.50(dd，J＝2.8Hz，J＝8.8Hz，1H)，4.50(s，2H)，4.05-4.01(m，2H)，3.76(s，3H)，3.59(t，J＝6.2Hz，2H)，2.16-2.09(m，2H)； ¹³CNMR(CDCl ₃)δ164.8，155.5，139.3，129.2，117.4，107.8，101.9，67.8，55.8，42.4，38.9，30.0。

4-(3-chloropropyl)-7-fluoro-4H-benzo [1,4] oxazine-3-ketone (81MF763b)

[0162] according to GP5 mixing 7-fluoro-4H-benzo [1,4] oxazine-3-ketone (81MF763) (and 0.263g, 1.57mmol), Cs ₂CO ₃(0.769g, 2.36mmol) (0.354g 1.73mmol), obtains the crude product of title compound (0.40g) with 3-chloro-propyl iodide; ¹H NMR (CDCl ₃) δ 7-01-6.91 (m, 1H), 6.79-6.73 (m, 2H), 4.60 (s, 2H), 4.08 (t, J=7.2Hz, 2H), 3.62 (t, J=6.4Hz, 2H), 2.18-2.11 (m, 2H).

4-(3-chloropropyl)-4H-pyrido [4,3-b] [1,4] thiazine-3-ketone (81MF939b)

[0163] according to GP5 mixing 4H-pyrido [4,3-b] [1,4] thiazine-3-ketone (81MF939a) (0.087g, 0.52mmol), Cs ₂CO ₃(0.256g, 0.78mmol) (0.116g 0.57mmol), obtains the crude product of title compound (0.139g) with 3-chloro-propyl iodide. ¹H?NMR(CDCl ₃)δ8.43(s，1H)，8.17(d，J＝5.2Hz，1H)，7.25(d，J＝5.2Hz，1H)，4.20-4.15(m，2H)，3.55(t，J＝6.2Hz，2H)，3.41(s，2H)，2.17-2.10(m，2H)。

Universal method 6 (GP6)

[0164] in the 100mL flask, adds 4H-benzo [1,4] oxazine-3-ketone (1.0 equivalent), the Cs that is dissolved in the dried MeCN of 50mL ₂CO ₃(1.5 equivalent) and 3-chloro-propyl iodide (1.1 equivalent), and at room temperature stir 72h.Reactant mixture is evaporated to dried, and uses 100mL H ₂The O dilution is with EtOAc (3 * 100mL) extractions.Merge organic layer, use MgSO ₄Drying is filtered, be evaporated to dried, with the CC (purification of heptane/EtOAc).

6,8-two chloro-4-(3-chloropropyl)-7-methyl-4H-benzo [1,4] oxazine-3-ketone (81MF2225b)

[0165] mix 6 according to GP6, and 8-two chloro-7-methyl-4H-benzo [1,4] oxazine-3-ketone (81MF2225a) (2.33g, 10.0mmol), Cs ₂CO ₃(4.88g, 15.0mmol) and 3-chloro-propyl iodide (2.25g, 11.0mmol).CC (SiO ₂Heptane/EtOAc 10: 1-5), obtain title compound (81MF2225b) (2.44g, 79%). ¹H?NMR(CDCl ₃)δ7.02(s，1H)，4.67(s，2H)，4.06(t，J＝7.2Hz，2H)，3.62(t，J＝6.2，2H)，2.43(s，3H)，2.18-2.10(m，2H)； ¹³CNMR(CDCl ₃)δ163.7，140.5，130.3，128.3，127.6，124.1，113.5，67.9，42.2，39.3，30.0，17.2。

4-(3-chloropropyl)-6,8-dimethyl-4H-benzo [1,4] oxazine-3-ketone (81MF2237b)

[0166] mix 6 according to GP6, and 8-dimethyl-4H-benzo [1,4] oxazine-3-ketone (81MF2237a) (1.70g, 9.60mmol), Cs ₂CO ₃(4.69g, 14.4mmol) and 3-chloro-propyl iodide (2.15g, 10.6mmol).CC (SiO ₂Heptane/EtOAc 10: 1-5), obtain title compound (81MF2237b) (0.96g, 39%). ¹H?NMR(CDCl ₃)δ6.72-6.69(m，2H)，4.56(s，2H)，4.07(t，2H)，3.62(t，J＝6.4Hz，2H)，2.30(s，3H)，2.20(s，3H)，2.19-2.12(m，2H)； ¹³C?NMR(CDCl ₃)δ164.9，141.5，131.9，128.0，126.7，126.4，113.1，67.8，42.5，39.0，30.3，21.2，15.5。

The 6-tert-butyl group-4-(3-chloropropyl)-4H-benzo [1,4] oxazine-3-ketone (81MF2248b)

[0167] according to the GP6 mixing 6-tert-butyl group-4H benzo [1,4] oxazine-3-ketone (81MF2248a) (and 2.07g, 10.0mmol), Cs ₂CO ₃(4.88g, 15.0mmol) and 3-chloro-propyl iodide (2.25g, 11.0mmol).CC (SiO ₂Heptane/EtOAc 10: 1-5), obtain title compound (81MF2248b) (1.39g, 49%). ¹H?NMR(CDCl ₃)δ7.12(d，J＝2.0Hz，1H)，7.03(dd，J＝8.4Hz，J＝2.0Hz，1H)，6.92(d，J＝8.4Hz，1H)，4.54(s，2H)，4.14(t，J＝7.2Hz，2H)，3.65(t，J＝6.0Hz，2H)，2.21-2.1?4(m，2H)，1.32(s，9H)； ¹³CNMR(CDCl ₃)δ164.8，146.4，143.1，127.9，120.9，116.7，112.2，67.8，42.6，38.9，34.8，31.6，30.2。

6-chloro-4-(3-chloropropyl)-7-nitro-4H-benzo [1,4] oxazine-3-ketone (81MF2253b)

[0168] according to GP6 mixing 6-chloro-7-nitro-4H-benzo [crude product of 1,4] oxazine-3-ketone (81MF2253a) (and 2.60g, 10.0mmol), Cs ₂CO ₃(4.88g, 15.0mmol) and 3-chloro-propyl iodide (2.25g, 11.0mmol).CC (SiO ₂Heptane/EtOAc 10: 1-5), obtain title compound (81MF2253b) (1.23g, 36%). ¹H?NMR(CDCl ₃)δ7.66(s，1H)，7.20(s，1H)，4.70(s，2H)，4.12(t，J＝7.6Hz，2H)，3.67-3.59(m，2H)，2.21-2.13(m，2H)； ¹³CNMR(CDCl ₃)δ163.6，143.5，133.3，133.2，122.4，117.2，115.2，67.4，42.1，39.6，29.8。

7-chloro-4-(3-chloropropyl)-4H-benzo [1,4] oxazine-3-ketone (81MF2271b)

[0169] according to GP6 mixing 7-chloro-4H-benzo [1,4] oxazine-3-ketone (81MF2271a) (and 1.74g, 9.47mmol), Cs ₂CO ₃(4.63g, 14.2mmol) and 3-chloro-propyl iodide (2.13g, 10.4mmol).CC (SiO ₂Heptane/EtOAc 10: 1-5), obtain title compound (81MF2271b) (1.95g, 79%). ¹H?NMR(CHCl ₃)δ7.03-6.96(m，3H)，4.59(s，2H)，4.07(t，J＝7.2Hz，2H)，3.61(t，J＝6.4Hz，2H)，2.17-2.10(m，2H)； ¹³C?NMR(CDCl ₃)δ164.0，146.0，129.1，127.3，123.0，117.8，115.5，67.7，42.4，39.2，30.0。

4-(3-chloropropyl)-5-methyl-4H-benzo [1,4] oxazine-3-ketone (81MF941b)

[0170] according to GP6 mixing 5-methyl-4H-benzo [1,4] oxazine-3-ketone (81MF941a) (and 1.514g, 9.28mmol), Cs ₂CO ₃(4.53g, 13.9mmol) and 3-chloro-propyl iodide (2.09g, 10.21mmol).CC (SiO ₂Heptane/EtOAc 10: 1-5), obtain title compound (81MF941b) (1.07g, 48%). ¹H?NMR(CHCl ₃)δ6.99-6.87(m，3H)，4.42(s，2H)，4.17(t，J＝7.2Hz，2H)，3.45(t，J＝6.4Hz，2H)，2.41(s，3H)，2.04-1.97(m，2H)； ¹³C?NMR(CHCl ₃)δ168.3，149.9，129.1，128.7，126.9，125.1，115.0，69.4，42.2，42.1，30.6，20.9。

4-(3-chloropropyl)-7-methyl-4H-benzo [1,4] oxazine-3-ketone (81MF2246b)

[0171] according to GP6 mixing 7-methyl-4H-benzo [1,4] oxazine-3-ketone (81MF2246a) (and 1.42g, 8.7mmol), Cs ₂CO ₃(4.24g, 13.0mmol) and 3-chloro-propyl iodide (1.95g, 9.5mmol).CC (SiO ₂Heptane/EtOAc 10: 1-5), obtain title compound (81MF2246b) (1.64g, 79%). ¹H?NMR(CHCl ₃)δ6.98-6.81(m，3H)，4.59(s，2H)，4.06-4.03(m，2H)，3.63-3.60(m，2H)，2.26(s，2H)，2.20-2.15(m，2H)； ¹³CNMR(CHCl ₃)δ164.8，145.8，134.3，123.9，118.1，114.9，68.0，42.8，39.4，30.5，21.0。

(R, S)-6-methyl-4-oxiranylmethyl radical-4H-benzo [1,4] oxazine-3-ketone (101IS84F1)

[0172] in doing the bottle of 7mL, add 6-methyl-4H-benzo [1,4] oxazine-3-ketone (and 160mg, 1.0mmol), chloropropylene oxide (0.147g, 1.6mmol), Cs ₂CO ₃(0.820g 2.5mmol) with dried DMF (1mL), shakes mixture 36h then under 60 ℃.With ether (20mL) diluted mixture thing, and water and saline (10mL) washing, drying is filtered, and concentrating under reduced pressure obtains grease.With quick CC (SiO ₂, CH ₂Cl ₂: purification acetone/MeOH 95: 3: 2) obtains title compound (0.127g, 39%). ¹H?NMR(CHCl ₃)δ7.01(d，J＝1.2Hz，1H)，6.84(d，J＝8.4Hz)，6.80(dm，J＝8.4Hz)，4.58(ABq?J＝15.2，21.2Hz，2H)，4.50(dd，J＝3.2，15.2Hz，1H)，3.66(dd，J＝6，15.2Hz)，3.23(m，1H)，2.86(dd，J＝4，4.4Hz，1H)，2.69(dd，J＝2.8，4.8Hz，1H)，2.33(s，3H)； ¹³C?NMR(CHCl ₃)δ156.2，143.3，132.9，129.0，124.9，116.9，116.6，68.0，50.2，25.8，44.0，21.3。

Universal method 7 (GP7)

[0173] in doing the 100mL flask, adds 4H-benzo [1,4] oxazine-3-ketone (1.0 equivalent), (3-bromo-2-methyl-propoxyl group)-tert-butyl group dimethylsilane (1.0 equivalent), the Cs that is dissolved among the dried DMF (40mL) ₂CO ₃(2.5 equivalent), and under 50 ℃, in noble gas, stirred 20-28 hour.In reaction, add entry (100mL), and (3 * 150mL) extract with ether.Merge organic layer, with saline (100mL) washing, Na ₂SO ₄Drying concentrates, and uses the CC (purification of heptane/EtOAc) then.

(S)-4-[3-(tert-butyl group dimethyl-silicon alcoxyl base)-2-methyl-propyl]-6-fluoro-4H-benzo [1,4] oxazine-3- Ketone (111MF01)

[0174] according to GP7 mixing 6-fluoro-4H-benzo [1,4] oxazine-3-ketone (95MF88) (2.54g, 15.2mmol), (R)-3-bromo-2-methyl propoxyl group-tert-butyl group dimethylsilane (4.07g, 15.2mmol) and Cs ₂CO ₃(12.38g, 38mmol).CC (SiO ₂Heptane/EtOAc 9: 1), obtain title compound (111MF01) (4.09g, 76%). ¹H?NMR(CHCl ₃)δ6.93-6.87(m，1H)，6.92-6.88(m，1H)，6.68-6.63(m，1H)，4.56(m，2H)，4.01(m，1H)，3.78(m，1H)，3.58(m，1H)，3.45(m，1H)，2.11(m，1H)，0.92(s，12H)，0.06(d，J＝0.8Hz，6H)； ¹³CNMR(CDCl ₃)δ164.8，158.5(d，J＝239.9Hz)，141.6(d，J＝2.7Hz)，130.1(d，J＝10.7Hz)，117.6(d，J＝9.3Hz)，109.6(d，J＝23.1Hz)，103.6(d，J＝28.8Hz)，67.8，65.9，44.2，34.5，26.0，18.4，14.9，-5.4，-5.4。

(S)-4-[3-(tert-butyl group dimethyl-silicon alcoxyl base)-2-methyl-propyl]-7-fluoro-4H-benzo [1,4] oxazine-3- Ketone (111MF14)

[0175] according to GP7 mixing 7-fluoro-4H-benzo [1,4] oxazine-3-ketone (111MF12) (2.52g, 15.1mmol), (S)-3-bromo-2-methyl propoxyl group-tert-butyl group dimethylsilane (4.03g, 15.1mmol) and Cs ₂CO ₃(12.3g, 38mmol).CC (SiO ₂Heptane/EtOAc 9: 1), obtain title compound (111MF14) (3.79g, 71%). ¹H?NMR(CDCl ₃)δ7.12(dd，J＝5.2Hz，J＝8.8Hz，1H)，6.67-6.34(m，2H)，4.60(q，J＝14.8Hz，J＝25.4Hz，2H)，4.03(dd，J＝8.4Hz，J＝14.0Hz，1H)，3.82(dd，J＝5.6Hz，J＝14.0Hz，1H)，3.57(dd，J＝4.8Hz，J＝10.0Hz，1H)，3.45(dd，J＝7.0Hz，J＝9.8Hz，1H)，2.15-2.05(m，1H)，0.93-0.89(m，12H)，0.06(s，6H)； ¹³C?NMR(CHCl ₃)δ164.1，158.9(d，J＝243.7Hz)，146.4(d，J＝11.6Hz)，125.3(d，J＝3.0Hz)，116.4(d，J＝9.6Hz)，109.1(d，J＝22.7Hz)，105.1(d，J＝25.8Hz)，67.8，66.0，44.1，34.5，26.0，18.4，14.9，-5.3，-5.4。

(S)-4-[3-(tert-butyl group dimethyl-silicon alcoxyl base)-2-methyl-propyl]-6-methoxyl group-4H-benzo [1,4] Evil Piperazine-3-ketone (111MF32)

[0176] according to GP7 mixing 6-methoxyl group-4H-benzo [1,4] oxazine-3-ketone (111MF24) (2.7g, 15.1mmol), (S)-3-bromo-2-methyl propoxyl group-tert-butyl group dimethylsilane (4.03g, 15.1mmol) and Cs ₂CO ₃(12.3g, 38mmol).CC (SiO ₂Heptane/EtOAc 9: 1), obtain title compound (111MF32) (4.03g, 80%). ¹H?NMR(CDCl ₃)δ?6.89(d，J＝8.8Hz，1H)，6.71(d，J＝2.8Hz，1H)，6.50(dd，J＝2.8Hz，J＝8.6Hz，1H)，4.53(q，J＝14.8Hz，J＝29.2Hz，2H)，3.98(dd，J＝8.8Hz，J＝14.0Hz，1H)，3.85(dd，J＝5.8Hz，J＝14.2Hz，1H)，3.77(s，3H)，3.57(dd，J＝9.2Hz，J＝10.0Hz，1H)，3.47(dd，J＝7.2Hz，J＝10.0Hz，1H)，2.20-2.12(m，1H)，0.91(s，12H)，0.05(d，J＝1.2Hz，6H)； ¹³C?NMR(CHCl ₃)δ165.3，155.6，139.7，129.8，117.2，107.4，103.3，68.0，66.2，55.9，43.9，34.3，26.1，18.5，14.7，-5.3，-5.4。

Universal method 8 (GP8)

[0177] in the 100mL flask, add 4-[3-(tert-butyl group dimethyl-silicon alcoxyl base)-2-methyl-propyl]-4H-benzo [1,4] oxazine-3-ketone (1.0 equivalent) and tetrabutyl ammonium fluoride monohydrate (1.3 equivalent), and be dissolved among the dried THF of 40mL.At room temperature in noble gas stirring reaction 20-24 hour.Concentrated reaction mixture, and with the CC (purification of heptane/EtOAc).

(S)-6-fluoro-4-(3-hydroxy-2-methyl propyl group)-4H-benzo [1,4] oxazine-3-ketone (111MF03)

[0178] according to GP8 mixing cpd (S)-4-[3-(tert-butyl group dimethyl-silicon alcoxyl base)-2-methyl-propyl]-6-fluoro-4H-benzo [1,4] oxazine-3-ketone (111MF01) (4.09g, 11.6mmol) and the tetrabutyl ammonium fluoride monohydrate (4.30g, 15.4mmol).CC (SiO ₂Heptane/EtOAc 4: 1-4), obtain title compound (111MF03) (2.63g, 95%). ¹H?NMR(CHCl ₃)δ6.92(dd，J＝5.2Hz，J＝8.8Hz，1H)，6.80(dd，J＝2.8Hz，J＝10.0Hz，1H)，6.71-6.66(m，1H)，4.59(d，J＝0.8Hz，2H)，4.17-4.11(m，1H)，3.58-3.40(m，3H)，2.79(s，1H)，2.08-1.96(m，1H)，1.04(d，J＝7.2Hz，3H)； ¹³C?NMR(CHCl ₃)δ165.3，158.4(d，J＝238.44Hz)，141.5(d，J＝2.7Hz)，129.5(d，J＝10.4Hz)，117.9(d，J＝9.3Hz)，110.2(d，J＝23.1Hz)，103.1(d，J＝28.4Hz)，67.5，63.85，43.8，34.0，14.9。

(S)-7-fluoro-4-(3-hydroxy-2-methyl propyl group)-4H-benzo [1,4] oxazine-3-ketone (111MF18)

[0179] according to GP8 mixing cpd (S)-4-[3-(tert-butyl group dimethyl-silicon alcoxyl base)-2-methyl-propyl group]-7-fluoro-4H-benzo [1,4] oxazine-3-ketone (111MF14) (3.79g, 10.7mmol) and the tetrabutyl ammonium fluoride monohydrate (3.99g, 14.3mmol).CC (SiO ₂Heptane/EtOAc 4: 1-4), obtain title compound (111MF18) (2.57g, 100%). ¹H?NMR(CHCl ₃)δ6.99-6.95(m，1H)，7.77-7.72(m，2H)，4.63(m，2H)，4.23-4.16(m，1H)，3.58-3.40(m，3H)，2.86(s，1H)，2.05-1.97(m，1H)，1.04(d，J＝6.8Hz，3H)； ¹³C?NMR(CHCl ₃)164.6，159.2(d，J＝244.5Hz)，146.4(d，J＝11.6Hz)，124.9(d，J＝3.1Hz)，115.9(d，J＝9.6Hz)，109.4(d，J＝22.7Hz)，105.3(d，J＝26.1Hz)，67.5，63.8，43.8，34.0，15.0。

(S)-4-(3-hydroxy-2-methyl propyl group)-6-methoxyl group-4H-benzo [1,4] oxazine-3-ketone (111MF34)

[0180] according to GP8 mixing cpd (S)-4-[3-(tert-butyl group dimethyl-silicon alcoxyl base)-2-methyl-propyl]-6-methoxyl group-4H-benzo [1,4] oxazine-3-ketone (111MF32) (4.03g, 12.0mmol) and the tetrabutyl ammonium fluoride monohydrate (4.46g, 16.0mmol).CC (SiO ₂Heptane/EtOAc 4: 1-4), obtain title compound (111MF34) (2.70g, 100%). ¹H?NMR(CHCl ₃)δ6.91(d，J＝8.8Hz，1H)，6.63(d，J＝2.8Hz，1H)，6.54(dd，J＝2.8Hz，J＝8.8Hz，1H)，4.57(s，2H)，4.19(dd，J＝9.4Hz，J＝14.6Hz，1H)，3.78(s，3H)，3.56-3.39(m，3H)，2.84(s，1H)，2.09-1.99(m，1H)，1.05(d，J＝7.2Hz，3H)； ¹³C?NMR(CHCl ₃)165.8，155.5，139.5，129.4，117.4，107.7，103.0，67.7，63.8，56.0，43.6，34.1，15.0。

Universal method 9 (GP9)

[0181] adding is dissolved in CHCl in the 250mL flask ₃4-(100mL) (3-hydroxy-2-methyl propyl group)-4H-benzo [1,4] oxazine-3-ketone (1.0 equivalent).Add triphenylphosphine (2.2 equivalent) and imidazoles (2.4 equivalent) then.In solution, add I ₂(2.8 equivalent), and at room temperature stirring reaction 15-18 hour.Reactant mixture Na ₂S ₂O ₃(saturated aqueous solution) (100mL) quencher.Separate each phase, water CH ₂Cl ₂(150mL) washing.Merge organic layer, use Na ₂SO ₄Drying concentrates, with the CC (purification of heptane/EtOAc).

(S)-6-fluoro-4-(3-iodo-2-methyl-propyl)-4H-benzo [1,4] oxazine-3-ketone (111MF04)

According to GP9 mixing cpd (S)-6-fluoro-4-(3-hydroxy-2-methyl-propyl group)-4H-benzo [1,4] oxazine-3-ketone (111MF03) (and 2.63g, 11.0mmol), triphenylphosphine (6.35g, 24.2mmol), imidazoles (1.8g, 26.4mmol) and I ₂(7.81g, 30.8mmol).CC (SiO ₂Heptane/EtOAc 9: 1-4), obtain title compound (111MF04) (3.86g, 100%). ¹H?NMR(CHCl ₃)δ6.97-6.93(m，1H)，6.82-6.78(m，1H)，6.73-6.68(m，1H)，4.63-4.53(m，2H)，3.90(d，J＝6.8Hz，2H)，3.20-3.16(m，2H)，2.15-2.04(m，1H)，1.06(d，J＝6.4Hz，3H)； ¹³CNMR(CHCl ₃)δ165.0，158.5(d，J＝240.2Hz)，141.7(d，J＝2.3Hz)，129.6(d，J＝10.4Hz)，118.1(d，J＝9.2Hz)，110.1(d，J＝23.4Hz)，103.1(d，J＝28.7Hz)，67.8，46.3，33.5，18.9，11.6。

(S)-7-fluoro-4-(3-iodo-2-methyl-propyl)-4H-benzo [1,4] oxazine-3-ketone (111MF20)

[0182] according to GP9 mixing cpd (S)-7-fluoro-4-(3-hydroxy-2-methyl propyl group)-4H-benzo [1,4] oxazine-3-ketone (111MF18) (2.57g, 11.0mmol), triphenylphosphine (6.61g, 23.7mmol), imidazoles (1.76g, 25.8mmol) and I2 (7.64g, 30.1mmol).CC (SiO ₂Heptane/EtOAc9: 1-4), obtain title compound (111MF20) (3.31g, 89%). ¹H?NMR(CDCl ₃)δ7.00-6.96(m，1H)，6.78-6.74(m，2H)，4.65-4.56(m，2H)，3.92(d，J＝7.6Hz，2H)，3.21-3.13(m，2H)，2.13-2.03(m，1H)，1.04(d，J＝6.4Hz，3H)； ¹³C?NMR(CHCl ₃)δ164.3，159.0(d，J＝244.4Hz)，146.6(d，J＝12.0Hz)，125.0(d，J＝3.0Hz)，115.9(d，J＝9.7Hz)，109.4(d，J＝22.5Hz)，105.5(d，J＝26.0Hz)，67.8，46.3，33.6，18.9，11.8。

(S)-4-(3-iodo-2-methyl-propyl)-6-methoxyl group-4H-benzo [1,4] oxazine-3-ketone (111MF36)

[0183] according to GP9 mixing cpd (S)-4-(3-hydroxy-2-methyl propyl group)-6-methoxyl group-4H-benzo [1,4] oxazine-3-ketone (111MF34) (2.70g, 12.0mmol), triphenylphosphine (6.92g, 26.4mmol), imidazoles (1.96g, 28.8mmol) and I ₂(8.53g, 33.6mmol).CC (SiO ₂Heptane/EtOAc 9: 1-4), obtain title compound (111MF36) (3.54g, 82%). ¹H?NMR(CDCl ₃)δ6.92(d，J＝8.4Hz，1H)，6.63(d，J＝2.8Hz，1H)，6.53(dd，J＝2.8Hz，J＝8.8Hz，1H)，4.54(q，J＝14.8Hz，J＝23.6Hz，2H)，3.92(d，J＝7.4Hz，2H)，3.80(s，3H)，3.18(dd，J＝1.0Hz，J＝6Hz，2H)，2.17-2.08(m，1H)，1.05(d，J＝6.8Hz，3H)； ¹³CNMR(CHCl ₃)δ165.4，155.6，139.6，129.4，117.7，108.0，102.5，68.0，56.1，46.1，33.6，18.9，12.0。

(S)-4-[3-(tert-butyl group dimethyl-silicon alcoxyl base)-2-methyl-propyl]-6-methyl-4H-benzo [1,4] oxazine -3-ketone (101IS60-1)

[0184] in dried 50mL round-bottomed flask, add 6-methyl-4H-benzo [1,4] oxazine-3-ketone (0.59g, 3.6mmol), (R)-(3-bromo-2-methyl propoxyl group)-tert-butyl group dimethylsilane (1.0g, 3.6mmol), Cs ₂CO ₃(2.9g, 8.9mmol) and the dried DMF of 10mL.Mixture stirs under 50 ℃ and spends the night (15h), with ether (50mL) dissolving, water (20mL) washing, and water ether (20mL) extraction.Merge organic facies, use the salt water washing then, dry (Na ₂SO ₄), filter concentrating under reduced pressure, the grease that obtains flash chromatography (SiO ₂Heptane/EtOAc 85: 15) purification obtains buttery title compound (1.1g, 88%). ¹H?NMR(CHCl ₃)δ6.87(d，J＝1.6Hz，1H)，6.81(d，J＝8.0Hz，1H)，6.72(dm，J＝8.0Hz，1H)，4.5(bars，2H)，3.93(dd，J＝8.8，14.0Hz，1H)，3.81(dd，J＝5.6，14.0Hz，1H)，3.53(dd，J＝4.8，10.2Hz，1H)，3.41(ddJ＝7.2，10.2Hz，1H)，2.25(s，3H)，2.18(m，1H)，0.87(s，9H)，0.83(d，J＝6.8Hz，3H)，0.01(s，6H)； ¹³C?NMR(CHCl ₃)δ170.5，148.9，137.8，129.6，122.2，121.6，73.3，71.6，49.0，39.7，31.5，26.6，23.8，20.1，0.0。

(S)-4-(3-hydroxy-2-methyl propyl group)-6-methyl-4H-benzo [1,4] oxazine-3-ketone (101IS60-2)

[01 85] are with chemical compound (S)-4-[3-(tert-butyl group dimethyl-silicon alcoxyl base)-2-methyl-propyl]-6-methyl-4H-benzo [1,4] oxazine-3-ketone (101IS60-1) (1.0g 2.9mmol) is dissolved in dried THF (12mL), and adding TBAF (1.2g, 3.8mmol).Reaction is at room temperature stirred and is spent the night, decompression concentrated solution, and remaining grease is with EtOAc (60mL) dilution, with saline (3 * 30mL) washings, dry (Na ₂SO ₄), filter concentrating under reduced pressure.Remaining grease flash chromatography (SiO ₂Heptane/EtOAc 30: 70) purification, obtaining can static crystalline grease (0.69g, 76%). ¹H?NMR(CHCl ₃)δ6.88(d，J＝8.4Hz，1H)，6.83-6.78(m，2H)，4.59(brs?2H)，4.22(dd?J＝10.0，14.4Hz)，3.57-3.38(m，3H)，2.9(vbrs，1H)，2.33(s，3H)，2.04(m，1H)，1.08(d，J＝7.2Hz)； ¹³C?NMR(CHCl ₃)δ165.7，143.4，132.3，124.9，117.1，115.9，67.6，63.7，43.5，34.2，21.3，15.1。

(S)-4-(3-iodo-2-methyl-propyl)-6-methyl-4H-benzo [1,4] oxazine-3-ketone (101IS70)

[0186] in dried 50mL round-bottomed flask, add (S)-4-(3-hydroxy-2-methyl propyl group)-6-methyl-4H-benzo [1,4] oxazine-3-ketone (and 1.0g, 4.2mmol), PPh ₃(2.2g, 8.5mmol), (0.58g 8.5mmol), and is dissolved in CH to imidazoles ₂Cl ₂(25mL).In 4h, add then in batches iodine (2.2g, 8.4mmol).After last the adding, reaction is poured over SiO ₂On, and filter.Concentrating under reduced pressure obtains the crude product (1.5g) of title compound, and it can use without being further purified.

1-(3-chloropropyl)-3,4-dihydro-1H-quinoline-4-ketone (85LM31)

[0187] adding is dissolved in DMF (50mL in the 50mL flask, do) in 3,4-dihydro-1H-quinoline-2-one-(2.00g, 13.6mmol) and sodium hydride (contain 60% in the oil, 0.712g, 16.3mmol), and at 0 ℃ of following 1h that stirs, (2.77g 13.6mmol), and at room temperature stirs 20h to add 1-chloro-3-iodo-propane then.Reactant mixture water (10mL) quencher, (3 * 25mL) extract product with EtOEt.Merge organic layer, dry (Na ₂SO ₄), evaporation is with quick CC (SiO ₂EtOAc/ heptane 1: 4) purification obtains the crude product (2.25g) of title compound (85,LM3 1). ¹H?NMR(CHCl ₃)δ7.29-7.22(m，1H)，7.17(d，J＝7.4Hz，1H)，7.08-6.98(m，2H)，4.10(t，J＝7.3Hz，CH ₂)，3.62(t，J＝5.9Hz，CH ₂)，2.88(t，J＝7.3Hz，CH ₂)，2.63(t，J＝7.3Hz，CH ₂)，2.19-2.10(m，2H)； ¹³C?NMR(CDCl ₃)δ170.5，140.0，128.2，127.8，126.3，123.2，115.0，43.3，40.2，32.2，30.5，26.0。

1-(3-chloropropyl)-6-fluoro-3,4-dihydro-1H-quinoline-2-one-(92LH79)

[0188] in argon, in reaction flask, add the 6-fluoro-3 that is dissolved in dried DMF (2mL), and 4-dihydro-1H-quinoline-2-one-(0.180g, 1.09mmol).Adding NaH (contain 60% in the oil, 0.048g, 1.20mmol), mixture at room temperature stirs 0.5h.(0.180g 1.14mmol), at room temperature stirs 20h then to add 1-bromo-3-chloropropane then.The quencher of reactant mixture water, product extracts with EtOAc.Merge organic layer, use Na ₂SO ₄Drying is filtered, and concentrates.Product is with quick CC (SiO ₂DCM) purification obtains title compound (92LH79) (0.193g, 73%). ¹H?NMR(CHCl ₃)δ7.02-6.88(m，3H)，4.09-4.05(m，2H)，3.61(t，J＝6.3Hz，CH ₂)，2.87(t，J＝6.7Hz，CH ₂)，2.65-2.61(m，2H)，2.16-2.09(m，2H)； ¹³C?NMR(CDCl ₃)δ169.8，158.4(J＝242.9Hz)，135.7(J＝2.7Hz)，128.5(J＝7.7Hz)，115.7(J＝8.1Hz)，115.1(J＝22.7)，113.8(J＝22.3Hz)，42.6，40.3，31.5，30.1，25.5。

(R, S)-1-(3-chloro-2-methyl-propyl)-6-fluoro-3,4-dihydro-1H-quinoline-2-one-(107LH68)

[0189] in argon, in reaction flask, add the 6-fluoro-3 that is dissolved in dried DMF (3mL), and 4-dihydro-1H-quinoline-2-one-(0.496g, 3.0mmol).Adding NaH (contain 60% in the oil, 0.132g, 3.3mmol), mixture at room temperature stirs 45min.Add then (R, S)-(0.513g 3.0mmol), at room temperature stirs 20h to 1-bromo-3-chloro-2-methylpropane then.The quencher of reactant mixture water, product extracts with i.Merge organic layer, use Na ₂SO ₄Drying is filtered, and concentrates.Crude product is with quick CC (SiO ₂EtOAc/ normal heptane 1: 1) purification obtains the crude product (0.308g) of title compound (107LH68).

1-(3-chloropropyl)-6-methyl-3,4-dihydro-1H-quinoline-2-one-(107LH14)

[0190] in argon, in reaction flask, add the 6-methyl-3 that is dissolved in dried DMF (5mL), and 4-dihydro-1H-quinoline-2-one-(107LH05) (0.300g, 1.26mmol).Adding NaH (contain 60% in the oil, 0.055g, 1.38mmol), mixture at room temperature stirs 1h.(0.198g 1.24mmol), at room temperature stirs 20h then to add 1-bromo-3-chloropropane then.The quencher of reactant mixture water, product extracts with EtOAc.Merge organic layer, use Na ₂SO ₄Drying is filtered, and concentrates.Crude product is with quick CC (SiO ₂DCM) purification obtains the crude product (0.257g) of title compound (107LH14).

1-(3-chloropropyl)-7-fluoro-6-methyl-3,4-dihydro-1H-quinoline-2-one-(112KK01)

[0191] in argon, in reaction flask, add the 7-fluoro-6-methyl-3 that is dissolved in dried DMF (5mL), and 4-dihydro-1H-quinoline-2-one-(97KK40) (0.102g, 0.57mmol).(0.015g, 0.63mmol), mixture at room temperature stirs 1h to add the NaH that washed.Add then the 1-chloro-3-iodopropane be dissolved in DMF (1mL) (0.104g, 0.51mmol).At room temperature stir 20h then.The quencher of reactant mixture water, product Et ₂The O extraction.Merge organic layer, use 4%MgSO ₄Solution washing is used Na ₂SO ₄Drying is filtered, and concentrates.Product is with quick CC (SiO ₂DCM/ normal heptane 2: 1, DCM, MeOH/DCM 1: 10) purification, obtain title compound (112KK01) (0.050g, 38%). ¹H?NMR(CHCl ₃)δ6.95-6.93(m，1H)，6.73(d，J＝11.5Hz，1H)，4.03-4.00(m，2H)，3.59(t，J＝6.5Hz，CH ₂)，2.83-2.79(m，2H)，2.62-2.58(m，2H)，2.20(d，J＝1.8Hz，CH ₃)，2.13-2.07(m，2H)。

1-(3-chloropropyl)-6,7-two fluoro-3,4-dihydro-1H-quinoline-2-one-(112KK03)

[0192] in argon, in reaction flask, add to be dissolved in and do 6 of DMF (5mL), 7-two fluoro-3,4-dihydro-1H-quinoline-2-one-(97KK47) (0.181g, 0.99mmol).(0.026g, 1.08mmol), mixture at room temperature stirs 0.5h to add the NaH that washed.(0.205g 1.00mmol), at room temperature stirs 20h then to add the 3-chloro-propyl iodide that is dissolved in DMF (1mL) then.The quencher of reactant mixture water, product Et ₂The O extraction.Merge organic layer, use 4%MgSO ₄Solution washing is used Na ₂SO ₄Drying is filtered, and concentrates.Product is with quick CC (SiO ₂DCM) purification obtains title compound (112KK03) (0.122g, 47%). ¹H?NMR(CD ₃OD)δ6.99-6.86(m，2H)，4.03-3.99(m，2H)，3.60(t，J＝6.1，CH ₂)，2.84-2.81(m，2H)，2.63-2.59(m，2H)，2.13-2.06(m，2H)。

1-(3-chloropropyl)-5-methyl-3,4-dihydro-1H-quinoline-2-one-and 1-(3-chloropropyl)-7-methyl-3,4-two Hydrogen-1H-quinoline-2-one-

[0193] (1.7g 8.5mmol) is heated to 135 ℃, adds AlCl in argon in the 30min in batches with tolyl acetamide (92LH85) between pure 2-chloro-N- ₃(3.4mg, 26mmol).Reaction is cooled to 60 ℃, add then HCl (10mL, 4M).(2 * 30mL) extractions merge organic facies to mixture, use Na with EtOAc ₂SO ₄Drying is filtered concentrating under reduced pressure.Residue flash chromatography (SiO ₂CH ₂Cl ₂/ MeOH 9: 1) purification obtains chemical compound 7-methyl-3,4-dihydro-1H-quinoline-2-one-and 5-methyl-3,4-dihydro-1H-quinoline-2-one-(1.1g).Mixture is dissolved among the dried DMF (8mL), and adding NaH (contain 60% in the oil, 310mg, 7.7mmol), solution is at N ₂In under room temperature, stir 45min.Add 1-bromo-3-chloropropane subsequently, reaction is at room temperature stirred and is spent the night.Reactant mixture dilutes with EtOAc (50mL), water (10mL) washing.Organic facies Na ₂SO ₄Drying is filtered concentrating under reduced pressure, residue obtains 1-(3-chloropropyl)-5-methyl-3,4-dihydro-1H-quinoline-2-one-(0.057g with preparation property RP-HPLC purification, 3%) 4-dihydro-1H-quinoline-2-one-(0.12g, 6%) and 1-(3-chloropropyl)-7-methyl-3.1-(3-chloropropyl)-5-methyl-3,4-dihydro-1H-quinoline-2-one-(107LH27-11.7): retention time=11.7min, ¹H NMR (CD ₃OD) δ 7.12 (vbrt, 7.7Hz, 1H), 6.98 (d, J=8.0Hz, 1H), 6.90 (d, J=7.2Hz, 1H), 4.09-4.02 (m, 2H), 3.59 (t, J=6.4Hz, 2H), 2.85-2.78 (m, 2H), 2.58-2.50 (m, 2H), 2.27 (s, 3H), 2.10-2.01 (m, 2H); ¹³C NMR (CD ₃OD) δ 171.5,139.2, and 135.9,126.9,125.4,125.3,113.1,42.2,40.1,31.1,30.3,21.2,18.5.1-(3-chloropropyl)-7-methyl-3,4-dihydro-1H-quinoline-2-one-(107LH27-13.1): retention time=13.1min, ¹H NMR (CD ₃OD) δ 7.02 (brd, J=7.6Hz, 1H), 6.94 (brs, 1H), 6.81 (brd, J=7.6Hz, 1H), 4.03 (brt, J=7.2Hz, 2H), 3.58 (t, J=6.2Hz, 2H), 2.78 (t, J=7.4Hz, 2H), 2.51 (t, J=7.4Hz), 2.30 (s, 3H), 2.09-2.00 (m, 2H); ¹³C NMR (CD ₃OD) δ 171.6,139.0, and 137.4,127.8,123.9,115.7,42.3,39.8,31.7,30.3,24.6,20.4.

(S)-and 1-[3-(tert-butyl group dimethylsilyl)-2-methyl-propyl]-3,4-dihydro-1H-quinoline-2-one- (122LH13)

[0194] in argon, in reaction flask, add to be dissolved in and do 3 of DMF (30mL), and 4-dihydro-1H-quinoline-2-one-(1.60g, 10.9mmol).Adding NaH (contain 60% in the oil, 0.480g, 12.0mmol), mixture at room temperature stirs 1h.(R)-(3.0g 10.9mmol), at room temperature stirred 4 days (3-bromo-2-methyl propoxyl group)-tert-butyl group dimethylsilane then in adding then.The quencher of reactant mixture water, product extracts with EtOAc.Merge organic layer, use Na ₂SO ₄Drying is filtered, and concentrates.Product is with quick CC (SiO ₂DCM) purification obtains title compound (122LH13) (2.685g, 74%).

(S)-and 1-(3-hydroxy-2-methyl propyl group)-3,4-dihydro-1H-quinoline-2-one-(122LH16)

[0195] in argon, in reaction flask, add (S)-1-[3-(tert-butyl group dimethylsilyl)-2-methyl-propyl that is dissolved in dried THF (20mL)]-3,4-dihydro-1H-quinoline-2-one-(122LH13) (2.685g, 8.05mmol) and tetrabutyl ammonium fluoride (2.70g, 10.3mmol), at room temperature stir 20h.Concentrated reaction mixture, product is with quick CC (SiO ₂Normal heptane/EtOAc 1: 1) purification obtains title compound (122) (1.54g, 87%).

(S)-and 1-(3-iodo-2-methyl-propyl)-3,4-dihydro-1H-quinoline-2-one-(122LH18)

[0196] in reaction flask, add (the S)-1-(3-hydroxy-2-methyl propyl group)-3 that is dissolved in 50mL DCM, and 4-dihydro-1H-quinoline-2-one-(122LH16) (1.54g, 7.0mmol).Add PPh ₃(4.04g, 15.4mmol) and imidazoles (1.14g 16.7mmol), at room temperature stirs 15min then.Use the ice bath cooling mixture, add I then ₂(5.00g, 19.7mmol).Reactant mixture slowly rises to room temperature, and stirring is spent the night.Reactant mixture Na ₂S ₂O ₃Solution washing is used Na ₂SO ₄Drying concentrates.Product is with quick CC (SiO ₂Normal heptane/EtOAc 1: 1) purification obtains title compound (122LH18) (2.140g, 93%).

1-(3-chloropropyl)-1H-quinoline-2-one-(107LH80)

[0197] in the 7mL bottle, add the 1H-quinoline-2-one-(0.62g, 4.2mmol), 4mL do DMF and NaH (contain 60% in the oil, 0.200g, 5.1mmol).Mixture is at N ₂In under room temperature, stir 45min, (0.42mL, 4.2mmol), reaction is at room temperature stirred and is spent the night to add 1-bromo-3-chloropropane subsequently.Reaction is diluted with EtOAc (50mL), water (15mL) washing.Water merges organic facies with EtOAc (25mL) extraction, dry (Na ₂SO ₄), filter concentrating under reduced pressure, residue flash chromatography (SiO ₂CH ₂Cl ₂) purification, obtaining title compound (0.38g, 41%), it contains 1-(3-bromopropyl)-1H-quinoline-2-one-of 15%. ¹H?NMR(CD ₃OD)δ7.90(d，J＝9.4Hz，1H)，7.73-7.57(m，3H)，7.34-7.28(m，1H)，6.66(d，J＝9.4Hz)，4.46(t，J＝7.4Hz，2H)，3.71(t，J＝6.4Hz，2H)，2.21-2.02(m，2H)； ¹³C?NMR(CD ₃OD)δ163.2，140.7，138.8，131.3，129.3，122.8，121.4，120.2，114.4，42.18，40.2，30.5。

1-(3-chloropropyl)-5-methyl isophthalic acid H-quinoline-2-one-(107LH39)

[0198] in the microwave bottle, add 1-(3-chloropropyl)-5-methyl-3,4-dihydro-1H-quinoline-2-one-(0.081g, 0.34mmol), DDQ (0.116g, 0.51mmol), dioxane (2mL), and sealing.Behind 175 ℃ of following microwave irradiation 10min, reaction is used saturated NaHCO with EtOAc (50mL) dilution ₃Aqueous solution (2 * 15mL) washings, dry organic facies (Na ₂SO ₄), filter, concentrating under reduced pressure, residue usefulness prepares property RP-HPLC purification, obtains the crude product (0.053g) of title compound, and it can use without being further purified.HPLC-MS (ammonium acetate) [M+H] ⁺=236.2.

1-(3-chloropropyl)-7-methyl isophthalic acid H-quinoline-2-one-(107LH40)

[0199] in the microwave bottle, add 1-(3-chloropropyl)-7-methyl-3,4-dihydro-1H-quinoline-2-one-(0.21g, 0.88mmol), DDQ (0.30g, 1.3mmol), dioxane (4mL), and sealing.Behind 175 ℃ of following microwave irradiation 10min, reaction is used saturated NaHCO with EtOAc (50mL) dilution ₃(Na is used in 2 * 15mL) washings to aqueous solution ₂SO ₄Dry organic facies is filtered concentrating under reduced pressure.Residue usefulness prepares property RP-HPLC purification, obtains the crude product (0.130g) of title compound, and it can use without being further purified.HPLC-MS (ammonium acetate) [M+H] ⁺=236.2.

(S)-1-[3-(tert-butyl group dimethyl-silicon alcoxyl base)-2-methyl-propyl]-1H-quinoline-2-one-(107LH43)

[0200] with the 1H-quinoline-2-one-(1.9g, 13mmol) and NaH (contain 60% in the oil, 0.58g 15mmol) is added to and does among the DMF (30mL), is reflected at N ₂In under room temperature, stir 45min.(3.7g 13mmol), is reflected at 50 ℃ and stirs 72h down to add (R)-(3-bromo-2-methyl-propyl)-tert-butyl group dimethylsilane subsequently.Reaction is poured in the water, and (2 * 50mL) extractions merge organic facies, and drying is filtered concentrating under reduced pressure with EtOAc.Residue flash chromatography (SiO ₂CH ₂Cl ₂) purification, obtain title compound (2.10g, 6.4mmol, 48%). ¹H?NMR(CDCl ₃)δ7.60-7.53(m，2H)，7.49-7.40(m，2H)，7.12(dt，J＝0.9，7.6Hz，1H)，6.62(d，J＝9.6Hz，1H)，4.39(dd，J＝8.4，14.0Hz，1H)，4.15(dd，J＝5.4，14.0Hz)，3.54(dd，J＝4.4，10.2Hz，1H)，3.45(dd，J＝7.6，10.2Hz)，2.27-2.12(m，1H)，0.88(s，12H)，0.01(s，6H)； ¹³CNMR(CHCl ₃)δ168.2，145.2，144.5，135.8，134.3，127.3，127.2，126.4，120.5，71.7，50.4，40.9，31.4，23.8，20.4，0.0。

(S)-1-(3-hydroxy-2-methyl propyl group)-1H-quinoline-2-one-(107LH62)

[0201] with TBAF (1.2g, 4.6mmol) and (S)-1-[3-(tert-butyl group dimethyl-silicon alcoxyl base)-2-methyl-propyl]-(0.31g 0.93mmol) is dissolved among the THF (5mL) the 1H-quinoline-2-one-, and stirs under room temperature in argon and spend the night.The concentrating under reduced pressure mixture, and be dissolved among the EtOAc (30mL).Na is used in solution with water (15mL) washing ₂SO ₄Drying, concentrating under reduced pressure.Its residue filters by silicon dioxide, obtains the crude product (0.19g) of title compound, and it can use without being further purified.

(S)-1-(3-iodo-2-methyl-propyl)-1H-quinoline-2-one-(107LH64)

[0202] with imidazoles (0.14g, 2.1mmol), (S)-1-(3-hydroxy-2-methyl-propyl group)-1H-quinoline-2-one-crude product (0.19g, 0.87mmol) and PPh ₃(0.50g 1.9mmol) is dissolved in CH ₂Cl ₂(5mL), and solution is chilled to 0 ℃, adds I subsequently ₂(0.61g, 2.4mmol), reaction is at room temperature spent the night.Reaction CH ₂Cl ₂(25mL) saturated Na is used in dilution ₂SO ₄(Na is used in 2 * 25mL) washings to aqueous solution ₂SO ₄Dry organic facies is filtered, and concentrating under reduced pressure obtains crude product, and it can use without being further purified.HPLC-MS (ammonium acetate) [M+H] ⁺=328.1.

Universal method 10 (GP10)

[0203] adding is dissolved in corresponding heterocyclic compound (1 equivalent) and the corresponding piperidines (1.2 or 2 equivalent) among the dried MeCN (1/2mL) and shakes in the 4mL bottle.Reactant mixture water (1mL) quencher, (2 * 1mL) extract product with EtOAc.Merge organic layer, with cation exchange CC and quick CC purification.

(R)-4-[3-(4-butyl piperidine base-1)-2-methyl-propyl]-4H-benzo [1,4] thiazine-3-ketone (108LM43-40)

[0204] makes chemical compound (S)-4-(3-iodo-2-methyl-propyl group)-4H-benzo [1 that is dissolved among the MeCN (1/2mL) according to GP10,4] thiazine-3-ketone (108LM37-34) (0.105g, 0.304mmol) and 4-butyl-piperidines (0.052g, 0.369mmol) reaction, and under 60 ℃, shook 3 days.With cation exchange CC and quick CC (SiO ₂MeOH/DCM 1: 20) purification obtains title compound (108LM43-40) (0.082g, 75%). ¹H NMR (CHCl ₃) δ 7.34 (d, J=9.1Hz, 1H), 7.25-7.17 (m, 2H), 7.02-6.95 (m, 1H), 4.15-3.99 (m, 2H), 3.35 (s, CH ₂), 2.83 (bd, J=10.4Hz, 1H), 2.68 (bd, J=10.4Hz, 1H), 2.20-2.05 (m, 2H), 2.00-1.85 (m, 2H), 1.82-1.73 (m, 1H), 1.67-1.55 (m, 2H), 1.30-1.14 (m, 9H), 0.88 (t, J=7.2, CH ₃), 0.82 (d, J=6.5Hz, CH ₃); ¹³C NMR (CHCl ₃) δ 166.0,139.2,128.8,127.1,124.8,123.5,118.9,63.8,55.5,54.4,47.7,36.6,36.1,32.9,32.8,32.1,29.4,29.3,23.2,16.7,14.4; HPLC-MS (ammonium acetate) [M+H] ⁺=361.3.

(R)-4-[2-methyl-3-(propyl group of 4-propoxyl group piperidyl-1-)]-4H-benzo [1,4] thiazine-3-ketone (108LM49-46)

[0205] makes chemical compound (S)-4-(3-iodo-2-methyl-propyl group)-4H-benzo [1 that is dissolved among the MeCN (1/2mL) according to GP10,4] thiazine-3-ketone (108LM37-34) (0.433g, 1.25mmol) and 4-propoxyl group piperidines (79KS66) (0.225g, 1.55mmol) reaction, and under 60 ℃, shook 4 days.With cation exchange CC and quick CC (SiO ₂MeOH/DCM 1: 20) purification obtains title compound (108LM49-46) (0.220g, 49%). ¹H NMR (CDCl ₃) δ 7.37 (d, J=8.1Hz, 1H), 7.25-7.20 (m, 2H), 7.05-6.97 (m, 1H), 4.18-4.00 (m, 2H), 3.42-3.35 (m, 4H), and 3.30-3.20 (m, 1H), 2.80-2.70 (m, 1H), and 2.65-2.55 (m, 1H), 2.20-2.05 (m, 3H), and 2.00-1.82 (m, 4H), 1.62-1.50 (m, 4H), 0.92 (t, J=7.4, CH ₃), 0.82 (d, J=6.8Hz, CH ₃), ¹³C NMR (CHCl ₃) δ 166.1,139.2,128.8,127.1,124.9,123.5,118.8,75.5,69.8,63.3,52.7,51.9,47.6,32.1,32.0,29.6,23.5,16.6,10.9; HPLC-MS (ammonium acetate) [M+H] ⁺=363.3.

(R)-4-[3-(4-butylidene-piperidyl-1)-2-methyl-propyl group]-4H-benzo [1,4] thiazine-3-ketone (108LM50-47)

[0206] makes chemical compound (S)-4-(3-iodo-2-methyl-propyl group)-4H-benzo [1 that is dissolved among the MeCN (1/2mL) according to GP10,4] thiazine-3-ketone (108LM37-34) (0.432g, 1.25mmol) and 4-butylidene piperidines (111MF05) (0208g, 1.49mmol) reaction, and under 60 ℃, shook 4 days.With cation exchange CC and quick CC (SiO ₂MeOH/DCM 1: 20) purification obtains title compound (108LM50-47) (0.267g, 60%). ¹H NMR (CHCl ₃) δ 7.35 (d, J=7.5Hz, 1H), 7.26-7.18 (m, 2H), 6.98 (t, J=7.5Hz, 1H), 5.10 (t, J=7.4Hz, CH), 4.17-4.03 (m, 2H), 3.36 (s, CH ₂), 2.43-2.33 (m, 2H), 2.30-2.08 (m, 8H), 2.00-1.90 (m, 3H), 1.28-1.38 (m, 2H), 0.90-0.80 (m, 6H); ¹³C NMR (CDCl ₃) δ 166.0,139.2,136.4,128.8,127.1,124.8,123.5,122.7,118.8,63.4,56.4,55.6,47.7,36.4,32.1,29.5,29.4,28.6,23.4,16.7,14.0; HPLC-MS (ammonium acetate) [M+H] ⁺=359.3.

(R)-4-[3-(3-butyl-8-aza-bicyclo [3.2.1] octyl group-8)-2-methyl-propyl group]-4H-benzo [1,4] thiophene Piperazine-3-ketone (108LM51-48)

[0207] makes chemical compound (S)-4-(3-iodo-2-methyl-propyl group)-4H-benzo [1 that is dissolved among the MeCN (1/2mL) according to GP10,4] thiazine-3-ketone (108LM37-34) (0.093g, 0.269mmol) and 3-butyl-8-aza-bicyclo [3.2.1] octane (104KS29) (0.054g, 0.323mmol) reaction, and under 40 ℃, shook 5 days.With cation exchange CC and quick CC (SiO ₂MeOH/DCM 1: 10) purification obtains title compound (108LM51-48) (0.042g, 40%). ¹H NMR (CHCl ₃) δ 7.38 (d, J=7.8Hz, 1H), 7.33 (d, J=8.1Hz, 1H), 7.22 (t, J=7.9Hz, 1H), 7.00 (t, J=8.0Hz, 1H), 4.18-4.10 (m, 2H), 3.38 (s, CH ₂), 3.15-3.00 (m, 2H), 2.30-2.22 (m, 1H), 2.20-2.10 (m, 1H), 1.90-1.75 (m, 3H), 1.60-1.40 (m, 5H), 1.40-1.15 (m, 8H), 0.90-0.82 (m, 6H); ¹³C NMR (CHCl ₃) δ 166.1,139.2,128.7,127.2,124.7,123.5,119.1,61.4,60.1,57.3,47.6,38.3,36.9,32.1,31.2,29.9,29.4,28.2,27.2,26.5,23.1,16.7,14.3; HPLC-MS (ammonium acetate) [M+H] ⁺=387.3.

(R)-4-[2-methyl-3-(propyl group of 3-amyl group-8-aza-bicyclo [3.2.1] octyl group-8-)]-4H-benzo [1,4] thiophene Piperazine-3-ketone (108LM52-49)

[0208] makes chemical compound (S)-4-(3-iodo-2-the methyl-propyl)-4H-benzo [1 that is dissolved among the MeCN (1/2mL) according to GP10,4] thiazine-3-ketone (108LM37-34) (0.080g, 0.231mmol) and 3-amyl group-8-azabicyclo [3.2.1] octane (104KS32-2) (0.050g, 0.276mmol) reaction, and under 40 ℃, shook 5 days.With cation exchange CC and quick CC (SiO ₂MeOH/DCM 1: 50+1%Et ₃N) purification obtains title compound (108LM52-49) (0.045g, 49%). ¹H NMR (CHCl ₃) δ 7.36 (d, J=7.6Hz, 1H), 7.32 (d, J=7.7Hz, 1H), 7.22 (t, J=7.6Hz, 1H), 7.00 (t, J=7.6Hz, 1H), 4.16 (d, J=7.3Hz, CH ₂), 3.34 (s, CH ₂), 3.10-2.95 (m, 2H), 2.25-2.17 (m, 1H), 2.15-2.03 (m, 3H), 1.94-1.75 (m, 3H), 1.70-1.60 (m, 1H), 1.60-1.50 (m, 2H), 1.40-1.15 (m, 10H), 0.90-0.80 (m, 6H); ¹³C NMR (CDCl ₃) δ 166.1,139.2,128.7,127.1,124.7,123.4,119.1,60.5,59.0,57.4,47.5,38.4,36.4,32.2,32.1,31.4,29.9,28.5,28.4,27.9,27.2,22.9,16.7,14.3; HPLC-MS (ammonium acetate) [M+H] ⁺=401.3.

Universal method 11 (GP11)

[0209] in the 100mL flask, adds 4-(3-chloropropyl)-4H-benzo [1,4] oxazine-3-ketone (1.0 equivalent), the K that is dissolved among the dried MeCN of 25mL ₂CO ₃(2.0 equivalent), NaI (2.0 equivalent) and 4-butyl piperidine (1.05 equivalent), and at N ₂In under room temperature, stir 168h.Reactant mixture is evaporated to dried, uses 100mL H ₂The O dilution is with EtOAc (3 * 120mL) extractions.Merge organic layer, use MgSO ₄Drying, be evaporated to dried, with CC (heptane: EtOAc or CH ₂Cl ₂: MeOH) purification.

4-[3-(propyl group of 4-butyl piperidine base-1-)]-6,8-two chloro-7-methyl-4H-benzo [1,4] oxazine-3-ketone (81MF2225F)

[0210] mix 6 according to GP11, and 8-two chloro-4-(3-chloropropyl)-7-methyl-4H-benzo [1,4] oxazine-3-ketone (81MF2225b) (2.44g, 7.92mmol), K ₂CO ₃(2.19g, 15.84mmol), NaI (2.37g, 15.84mmol) and the 4-butyl piperidine (1.172g, 8.3mmol).CC (SiO ₂Heptane/EtOAc 10: 1-4) purification obtains title compound (81MF2225F) (1.55g, 47%). ¹HNMR(CHCl ₃)δ7.11(s，1H)，4.65(s，2H)，3.93(t，2H)，2.86，(d，2H)，2.41(s，3H)，2.41(s，3H)，2.33(t，2H)，1.92-1.77(m，4H)，1.65(d，2H)，1.31-1.19(m，9H)，0.88(t，3H)； ¹³C?NMR(CHCl ₃)δ163.5，140.5，129.9，128.1，123.7，114.0，67.9，55.8，54.4，40.1，36.4，36.0，32.6，29.2，24.8，23.1，17.2，14.2。

[0211] to the pure compound that is dissolved in ether (4mL) (0.235g, add in 0.50mmol) oxalic acid be dissolved in ether (2mL) (0.047g, 0.52mmol).Filter the crystal that forms,, obtain the oxalates (0.24g, 94%) of title compound with the ether washing; HPLC-MS (ammonium acetate) [M+H] ⁺=413.2.

4-[3-(propyl group of 4-butyl-piperidyl-1-)]-6,8-dimethyl-4H-benzo [1,4] oxazine-3-ketone (81MF2237F)

[0212] according to GP11 mixing 4-(3-chloropropyl)-6, and 8-dimethyl-4H-benzo [1,4] oxazine-3-ketone (81MF2237b) (0.96g, 3.78mmol), K ₂CO ₃(1.05g, 7.57mmol), NaI (1.14g, 7.57mmol) and the 4-butyl piperidine (0.56g, 3.97mmol).CC (SiO ₂Heptane/EtOAc 10: 1-4) purification obtains title compound (81MF2237F) (0.98g, 72%). ¹H?NMR(CDCl ₃)δ6.71(s，1H)，6.65(s，1H)，4.52(s，2H)，3.93(t，J＝7.2，2H)，2.87(d，J＝11.2，2H)，2.36(t，J＝7.2Hz，2H)，2.27(s，3H)，2.18(s，3H)，1.81-1.89(m，4H)，1.65(d，J＝9.6Hz，2H)，1.28-1.17(m，9H)，0.87(t，J＝6-8Hz，3H)； ¹³C?NMR(CDCl ₃)δ164.6，141.4，131.6，128.3，126.3，126.1，113.4，67.8，56.1，54.3，39.8，36.4，35.9，32.7，29.1，25.0，23.0，21.1，15.5，14.2。

[0213] to the pure compound that is dissolved in ether (4mL) (0.193g, add in 0.54mmol) oxalic acid be dissolved in ether (2mL) (0.051g, 0.57mmol).Filter the crystal that forms,, obtain the oxalates (0.22g, 91%) of title compound with the ether washing; HPLC-MS (ammonium acetate) [M+H] ⁺=359.3.

The 6-tert-butyl group-4-[3-(propyl group-4H-benzo [1,4] oxazine-3-ketone of 4-butyl z piperidyl-1-) (81MF2248F)

[0214] according to the GP11 mixing 6-tert-butyl group-4-(3-chloropropyl)-4H-benzo [1,4] oxazine-3-ketone (81MF2248b) (and 1.39g, 4.93mmol), K ₂CO ₃(1.36g, 9.85mmol), NaI (1.48g, 9.85mmol) and the 4-butyl piperidine (0.73g, 5.17mmol).CC (SiO ₂Heptane/EtOAc 10: 1-4) purification obtains title compound (81MF2248F) (1.66g, 87%). ¹H?NMR(CHCl ₃)δ7.01-6.98(m，2H)，6.91-6.88(m，1H)，4.55(s，2H)，3.99(t，J＝7.2Hz，2H)，2.89(d，J＝6.4Hz，2H)，2.42(t，J＝6.8Hz，2H)，1.92-1.82(m，4H)，1.65(d，J＝9.6Hz?2H)，1.31(s，9H)，1.29-1.17(m，9H)，0.88(t，J＝6.8Hz，3H)； ¹³CNMR(CDCl ₃)δ164.6，146.1，143.3，128.1，120.6，116.6，112.2，67.9，56.5，54.4，39.8，36.4，35.9，34.7，32.6，31.6，29.2，24.8，23.1，14.2。

[0215] to the pure compound that is dissolved in ether (4mL) (0.178g, add in 0.46mmol) oxalic acid be dissolved in ether (2mL) (0.044g, 0.49mmol).Filter the crystal that forms,, obtain the oxalates (0.19g, 87%) of title compound with the ether washing; HPLC-MS (ammonium acetate) [M+H] ⁺=387.4.

4-[3-(propyl group of 4-butyl piperidine base-1-)]-5-methyl-4H-benzo [1,4] oxazine-3-ketone (81MF941x)

[0216] according to GP11 mixing 4-(3-chloropropyl)-5-methyl-4H-benzo [1,4] oxazine-3-ketone (81MF941b) (and 1.08g, 4.48mmol), K ₂CO ₃(1.24g, 8.95mmol), NaI (1.34g, 8.95mmol) and the 4-butyl piperidine (0.66g, 4.70mmol).CC (SiO ₂Heptane/EtOAc 10: 1-4) purification obtains title compound (81MF941x) (0.814g, 53%). ¹H?NMR(CDCl ₃)δ6.97-6.83(m，3H)，4.41(s，2H)，4.07(t，J＝7.2Hz，2H)，2.67(d，J＝10.8Hz，2H)，2.39(s，3H)，2.18(t，J＝7.2Hz，2H)，1.76(t，J＝10.8Hz，2H)，1.69-1.62(m，2H)，1.58(d，J＝10.0Hz，2H)，1.30-1.06(m，9H)，0.87(t，J＝6.8Hz，3H)； ¹³CNMR(CDCl ₃)δ168.3，150.0，129.2，128.9，126.8，124.8，114.8，69.5，55.7，54.2，42.6，36.4，35.9，32.6，29.2，25.3，23.0，20.9，14.2。

[0217] to the pure compound that is dissolved in ether (4mL) (0.177g, add in 0.52mmol) oxalic acid be dissolved in ether (2mL) (0.047g, 0.49mmol).Filter the crystal that forms,, obtain the oxalates (0.21g, 92%) of title compound with the ether washing; HPLC-MS (ammonium acetate) [M+H] ⁺=345.1.

4-[3-(propyl group-7-methyl-4H-benzo [1, the 4] oxazine-3-ketone (81MF2246F) of 4-butyl piperidine base-1-)

[0218] according to GP11 mixing 4-(3-chloropropyl)-7-methyl-4H-benzo [1,4] oxazine-3-ketone (81MF2246b) (and 1.64g, 6.84mmol), K ₂CO ₃(1.89g, 13.68mmol), NaI (2.05g, 13.68mmol) and the 4-butyl piperidine (1.02g, 7.18mmol).CC (SiO ₂Heptane/EtOAc 10: 1-4) purification obtains title compound (81MF2246F) (1.85g, 79%). ¹H?NMR(CDCl ₃)δ6.97(d，J＝8.0Hz，1H)，6.82-6.78(m，2H)，4.54(s，2H)，3.94(t，J＝7.2Hz，2H)，2.86(d，J＝10.8Hz，2H)，2.37(t，J＝7.0Hz，2H)，2.28(s，3H)，1.92-1.79(m，4H)，1.66(d，J＝9.2Hz，2H)，1.31-1.18(m，9H)，0.88(t，J＝7.2Hz，3H)； ¹³C?NMR(CDCl ₃)δ164.2，145.3，133.9，126.3，123.3，117.7，115.0，67.8，56.0，54.3，39.7，36.5，36.0，32.7，29.2，24.9，23.1，20.8，14.2。

[0219] to the pure compound that is dissolved in ether (4mL) (0.156g, add in 0.45mmol) oxalic acid be dissolved in ether (2mL) (0.042g, 0.47mmol).Filter the crystal that forms,, obtain the oxalates (0.192g, 97%) of title compound with the ether washing; HPLC-MS (ammonium acetate) [M+H] ⁺=345.1.

4-[3-(propyl group of 4-butyl piperidine base-1-)]-6-chloro-7-nitro-4H-benzo [1,4] oxazine-3-ketone (81MF2253x)

[0220] according to GP11 mixing 6-chloro-4-(3-chloropropyl)-7-nitro-4H-benzo [1,4] oxazine-3-ketone (81MF2253b) (and 1.23g, 4.05mmol), K ₂CO ₃(1.12g, 8.09mmol), NaI (1.21g, 8.09mmol) and the 4-butyl piperidine (0.60g, 4.24mmol).CC (SiO ₂Heptane/EtOAc 10: 1-4) purification obtains title compound (81MF2253x) (0.698g, 42%). ¹H?NMR(CDCl ₃)δ7.61(s，1H)，7.36(s，1H)，4.66，(s，2H)，3.99(t，J＝6.8Hz，2)，2.85(d，J＝11.2Hz，2H)，2.34(t，J＝6.4Hz，2H)，1.94-1.80(m，4H)，1.67(d，J＝10.0Hz，2H)，1.31-1.20(m，9H)，0.88(t，J＝6.4Hz，3H)； ¹³C?NMR(CHCl ₃)δ163.4，143.4，141.9，133.9，122.1，117.7，114.8，67.5，55.5，54.4，40.5，36.4，36.0，32,6，29.2，24.6，23.0，14.2。

[0221] to the pure compound that is dissolved in ether (4mL) (0.128g, add in 0.31mmol) oxalic acid be dissolved in ether (2mL) (0.029g, 0.33mmol).Filter the crystal that forms,, obtain the oxalates (0.125g, 80%) of title compound with the ether washing; HPLC-MS (ammonium acetate) [M+H] ⁺=410.1.

4-[3-(propyl group of 4-butyl piperidine base-1-)]-7-chloro-4H-benzo [1,4] oxazine-3-ketone (81MF2271x)

[0222] according to GP11 mixing 7-chloro-4-(3-chloropropyl)-4H-benzo [1,4] oxazine-3-ketone (81MF2271b) (and 1.953g, 7.49mmol), K ₂CO ₃(2.07g, 14.9mmol), NaI (2.24g, 14.9mmol) and the 4-butyl piperidine (1.11g, 7.86mmol).CC (SiO ₂Heptane/EtOAc 10: 1-4) purification obtains title compound (81MF2271x) (2.46g, 90%). ¹H?NMR(CHCl ₃)δ7.08-6.96(m，3H)，4.57(s，2H)，3.95(t，J＝7.2Hz，2H)，2.85(d，J＝10.8Hz，2H)，2.35(t，J＝7.2Hz，2H)，1.93-1.78(m，4H)，1.66(d，J＝9.2Hz，2H)，1.31-1.18(m，9H)，0.88(t，J＝6.4Hz，3H)； ¹³C?NMR(CHCl ₃)δ163.7，146.0，128.7，127.7，122.7，117.6，116.1，67.7，55.9，54.3，39.9，36.5，36.0，32.7，29.2，24.8，23.1，14.2。

[0223] to the pure compound that is dissolved in ether (4mL) (0.171g, add in 0.47mmol) oxalic acid be dissolved in ether (2mL) (0.043g, 0.49mmol).Filter the crystal that forms,, obtain the oxalates (0.206g, 97%) of title compound with the ether washing; HPLC-MS (ammonium acetate) [M+H] ⁺=365.1.

Universal method 12 (GP12)

[0224] in the 4mL bottle, adds 4-(3-chloropropyl)-4H-benzo [1,4] oxazine-3-ketone (1.0 equivalent), the K that is dissolved among the dried MeCN of 3mL ₂CO ₃(2.0 equivalent), NaI (2.0 equivalent) and amine (1.05 equivalent), and shake 100h at 60 ℃.Reactant mixture is evaporated to dried, uses 4mL H ₂CH is used in the O dilution ₂Cl ₂(3 * 10mL) extractions are filtered with PTFF Whatman filter.Merge organic layer, be evaporated to dried, with CC (heptane/EtOAc or CH ₂Cl ₂/ MeOH) or preparation property TLC (heptane/EtOAc or CH ₂Cl ₂/ MeOH) purification.

4-[3-(propyl group of 4-butyl piperidine base-1-)]-6-fluoro-4H-benzo [1,4] oxazine-3-ketone (8173MF55F)

[0225] according to GP12 mixing 4-(3-chloropropyl)-6-fluoro-4H-benzo [1,4] oxazine-3-ketone (8173MF55b) (and 0.102g, 0.42mmol), K ₂CO ₃(0.12g, 0.84mmol), NaI (0.13g, 0.84mmol) and the 4-butyl piperidine (0.06g, 0.44mmol).CC (SiO ₂Heptane/EtOAc 10: 1-4) purification obtains title compound (8183MF55F) (0.12g, 80%). ¹H?NMR(CHCl ₃)δ6.96(dd，J＝10.4Hz，J＝2.8Hz，1H)，6.87(dd，J＝9.6Hz，J＝5.2Hz，1H)，6.66-6.12(m，1H)，4.51(s，2H)，3.91(t，J＝7.2Hz，2H)，2.84(d，J＝11.2Hz，2H)，2.32(t，J＝7.2Hz，2H)，1.91-1.77(m，4H)，1.64(d，J＝9.6Hz，2H)，1.29-1.16(m，9H)，0.86(t，J＝6.8Hz，3H)； ¹³C?NMR(CHCl ₃)δ164.2，158.5(d，J＝239.5Hz)，141.4(d，J＝2.7Hz)，130.0(d，J＝10.4Hz)，117.5(J＝9.3Hz)，109.5(d，J＝23.5Hz)，103.2(d，J＝28.8Hz)，67.7，55.7，54.3，40.0，36.4，35.9，32.6，29.1，24.7，23.0，14.2。

[0226] to the pure compound that is dissolved in ether (4mL) (0.12g, add in 0.34mmol) oxalic acid be dissolved in ether (2mL) (0.032g, 0.37mmol).Filter the crystal that forms,, obtain the oxalates (0.128g, 87%) of title compound with the ether washing.HPLC-MS (ammonium acetate) [M+H] ⁺=349.2.

4-[3-(propyl group of 4-butyl piperidine base-1-)]-7,8-two fluoro-4H-benzo [1,4] oxazine-3-ketone (81MF2082x)

[0227] according to GP12 mixing 4-(3-chloropropyl)-7, and 8-two fluoro-4H-benzo [1,4] oxazine-3-ketone (81MF2082b) (0.16g, 0.60mmol), K ₂CO ₃(0.17g, 11.9mmol), NaI (0.18g, 11.9mmol) and the 4-butyl piperidine (0.09g, 0.63mmol).CC (SiO ₂Heptane/EtOAc 10: 1-4) purification obtains title compound (81MF2082x) (0.14g, 65%). ¹H?NMR(CHCl ₃)δ6.88-6.76(m，2H)4.66(s，2H)，3.96(t，J＝7.2Hz，2H)，2.84(d，J＝11.2，2H)，2.34(t，J＝6.8Hz，2H)，1.91-1.78(m，4H)，1.67(d?J＝9.6Hz，2H)，1.30-1.15(m，9H)； ¹³C?NMR(CDCl ₃)δ163.1，147.4(q，J＝245.0Hz，J＝10.6Hz)，140.1(q，J＝248.7Hz，J＝15.7Hz)，135.4(d，J＝12.0Hz)，126.5，109.5(d，J＝18.4Hz)，109.0(q，J＝7.6Hz，J＝3.8Hz)，67.8，55.8，52.3，40.1，36.4，35.9，32.7，29.1，24.8，23.0，14.2。

[0228] to the pure compound that is dissolved in ether (4mL) (0.14g, add in 0.39mmol) oxalic acid be dissolved in ether (2mL) (0.042g, 0.46mmol).Filter the crystal that forms,, obtain the oxalates (0.16g, 89%) of title compound with the ether washing.HPLC-MS (ammonium acetate) [M+H] ⁺=367.3.

4-[3-(propyl group of 4-butyl piperidine base-1-)]-4H-pyrido [4,3-b] [1,4] thiazine-3-ketone (81MF939)

[0229] according to GP12 mixing 4-(3-chloropropyl)-4H-pyrido [4,3-b] [1,4] thiazine-3-ketone (81MF939b) (0.14g, 0.57mmol), K ₂CO ₃(0.16g, 11.4mmol), NaI (0.18g, 11.4mmol) and the 4-butyl piperidine (0.09g, 0.60mmol).CC (SiO ₂Heptane/EtOAc 10: 1-4) purification obtains title compound (81MF939) (0.064g, 32%). ¹H?NMR(CDCl ₃)δ8.48(s，1H)，8.17(d，J＝5.2Hz，1H)，7.25(d，J＝4.8Hz，1H)，4.06-4.12(m，2H)，3.41(s，2H)，2.82(d，7＝11.2，2H)，2.33(t，J＝6.8Hz，2H)，1.83-1.89(m，4H)，1.64(d，J＝9.2Hz，2H)，1.16-1.29(m，9H)，0.87(t，J＝6.8Hz，3H)； ¹³C?NMR(CDCl ₃)δ163.91，143.84，138.92，136.20，134.04，122.31，55.80，54.32，43.29，36.43，35.99，32.68，30.78，29.19，25.20，23.05，14.24。

[0230] to the pure compound that is dissolved in ether (4mL) (0.064g, add in 0.18mmol) oxalic acid be dissolved in ether (2mL) (0.020g, 0.22mmol).Filter the crystal that forms,, obtain the oxalates (0.16g, 89%) of title compound with the ether washing; HPLC-MS (ammonium acetate) [M+H] ⁺=348.2.

4-[3-(propyl group of 4-propoxyl group piperidyl-1-)]-4H-benzo [1,4] thiazine-3-ketone (81MF07KS)

[0231] according to GP12 mixing 4-(3-chloropropyl)-4H-benzo [1,4] thiazine-3-ketone (81MF07) (0.18g, 0.74mmol), K ₂CO ₃(0.20g, 14.8mmol), NAI (0.22g, 14.8mmol) and 4-propoxyl group piperidines (0.12g, 0.81mmol).CC (SiO ₂Heptane/EtOAc 4: 1-4) purification obtains title compound (81MF07KS) (0.205g, 79%). ¹H?NMR(CHCl ₃)δ7.33(d，J＝7.6Hz，2H)，7.21(d，J＝3.2Hz，2H)，7.00-6.96(m，1H)，4.03(t，J＝7.2Hz，2H)，3.38-3.34(m，4H)，3.26-3.21(m，1H)，2.69(t，J＝5.6Hz，2H)，2.33(t，J＝7.2Hz，2H)，2.04(t，J＝9.8Hz，2H)，1.86-1.76(m，4H)，1.58-1.51(m，4H)，0.90(t，J＝7.2Hz，3H)； ¹³C?NMR(CHCl ₃)δ165.2，139.7，128.5，127.2，124.1，123.4，118.1，75.2，69.7，55.4，51.5，43.2，31.8，31.7，25.3，23.4，10.8。

[0232] to the pure compound that is dissolved in ether (4mL) (0.205g, add in 0.58mmol) oxalic acid be dissolved in ether (2mL) (0.058g, 0.64mmol).Filter the crystal that forms,, obtain the oxalates (0.192g, 74%) of title compound with the ether washing.HPLC-MS (ammonium acetate) [M+H] ⁺=349.2.

4-[3-(propyl group of 4-propoxyl group piperidyl-1-)]-4H-benzo [1,4] oxazine-3-ketone (81 (81MF08KS)

[0233] according to GP12 mixing 4-(3-chloropropyl)-4H-benzo [1,4] oxazine-3-ketone (81MF08) (and 0.13g, 0.58mmol), K ₂CO ₃(0.16g, 1.15mmol), NaI (0.17g, 1.15mmol) and 4-propoxyl group piperidines (0.089g, 0.60mmol).CC (SiO ₂Heptane/EtOAc4: 1-4) purification obtains title compound (81 (81MF08KS)) (0.147g, 76%). ¹HNMR(CDCl ₃)δ7.11-7.08(m，1H)，7.01-6.94(m，3H)，4.55(s，2H)，3.96(t，J＝7.2Hz，2H)，3.37(t，J＝6.8Hz，2H)，3.28-3.21(m，1H)，2.74-2.69(m，2H)，2.36(t，J＝7.2Hz，2H)，2.10-2.03(m，2H)，1.90-1.77(m，4H)，1.61-1.51(m，4H)，0.90(t，J＝7.2Hz，3H)； ¹³C?NMR(CDCl ₃)δ164.3，145.4，128.7，123.8，122.8，117.1，115.1，75.1，69.6，67.7，55.5，51.5，39.6，31.6，24.9，23.4，10.7。

[0234] to the pure compound that is dissolved in ether (4mL) (0.147g, add in 0.44mmol) oxalic acid be dissolved in ether (2mL) (0.048g, 0.53mmol).Filter the crystal that forms,, obtain the oxalates (0.160g, 86%) of title compound with the ether washing.HPLC-MS (ammonium acetate) [M+H] ⁺=333.3.

4-[3-(propyl group of 4-butyl piperidine base-1-)]-7-fluoro-4H-benzo [1,4] oxazine-3-ketone (81MF763)

[0235] according to GP12 mixing 4-(3-chloropropyl)-7-fluoro-4H-benzo [1,4] oxazine-3-ketone (81MF763b) (and 0.40g, 1.6mmol), K ₂CO ₃(0.44g, 3.2mmol), NaI (0.48g, 3.2mmol) and the 4-butyl piperidine (0.24g, 1.70mmol).CC (SiO ₂Heptane/EtOAc 4: 1-4) purification obtains title compound (81MF763) (0.26g, 46%). ¹H?NMR(CDCl ₃)δ7.09-7.04(m，1H)，6.74-6.69(m，2H)，4.58(s，2H)，3.95(t，J＝7.2Hz，2H)，2.84(d，J＝11.2Hz，2H)，3.45(t，J＝6.8Hz，2H)，1.91-1.78(m，4H)，1.66(d，J＝9.2Hz，2H)，1.29-1.16(m，9H)，0.88(t，7.2Hz，3H)； ¹³C?NMR(CDCl ₃)δ163.6，158.9(d，J＝243.7Hz)，146.3(d，J＝11.5Hz)，125.2(d，J＝3.0Hz)，115.9(d，J＝9.7Hz)，109.1(d，J＝22.8Hz)，105.1(d，J＝26.1Hz)，67.8，55.9，54.3，39.9，36.5，36.0，32.7，29.2，24.8，23.1，14.2。

[0236] to the pure compound that is dissolved in ether (4mL) (0.26g, add in 0.74mmol) oxalic acid be dissolved in ether (2mL) (0.073g, 0.818mmol).Filter the crystal that forms,, obtain the oxalates (0.26g, 78%) of title compound, HPLC-MS (ammonium acetate) [M+H] with the ether washing ⁺=349.3.

4-[3-(propyl group of 4-butylidene piperidyl-1-)]-4H-benzo [1,4] thiazine-3-ketone (81MF26)

[0237] according to GP12 mixing 4-(3-chloropropyl)-4H-benzo [1,4] thiazine-3-ketone (81MF07) (0.073g, 0.30mmol), K ₂CO ₃(0.12g, 0.90mmol), NaI (0.090g, 0.6mmol) and 4-butylidene piperidines (0.050g, 0.28mmol).Preparation property TLC (SiO ₂CH ₂Cl ₂/ MeOH 10: 1) purification obtains title compound (81MF26) (0.034g, 33%). ¹HNMR(CDCl ₃)δ7.34-7.31(m，1H)，7.23-7.20(m，1H)，7.00-6.95(m，1H)，5.10(t，J＝7.2Hz，1H)，4.04(t，J＝7.2Hz，2H)，3.34(s，2H)，2.37-2.32(m，6H)，2.23-2.14(m，2H)，1.96-1.90(m，2H)，1.86-1.78(m，2H)，1.37-1.27(m，2H)，0.86(t，J＝7.2Hz，3H)； ¹³C?NMR(CHCl ₃)δ165.1，139.6，136.0，128.5，127.2，124.1，123.4，122.7，118.1，55.6，55.4，54.8，43.2，36.1，31.7，29.2，28.3，25.2，23.2，13.8。

[0238] to the pure compound that is dissolved in ether (4mL) (0.034g, add in 0.10mmol) oxalic acid be dissolved in ether (2mL) (0.010g, 0.10mmol).Filter the crystal that forms,, obtain the oxalates (0.030g, 69%) of title compound with the ether washing; HPLC-MS (ammonium acetate) [M+H] ⁺=345.2.

4-[3-(propyl group of 4-butylidene piperidyl-1-)]-4H-benzo [1,4] oxazine-3-ketone (81MF25)

[0239] according to GP12 mixing 4-(3-chloropropyl)-4H-benzo [1,4] oxazine-3-ketone (81MF08) (and 0.068g, 0.30mmol), K ₂CO ₃(0.12g, 0.90mmol), NaI (0.090g, 0.60mmol) and 4-butylidene piperidines (0.050g, 0.28mmol).Preparation property TLC (SiO ₂CH ₂Cl ₂/ MeOH 10: 1) purification obtains title compound (81MF25) (0.070g, 71%). ¹HNMR(CDCl ₃)δ7.12(d，J＝6.8Hz，1H)，7.03-6.95(m，3H)，5.12(J＝7.4Hz，1H)，4.56(s，1H)，3.99(t，J＝7.6Hz，2H)，2.41-2.36(m，6H)，2.26-2.17(m，2H)，1.98-1.81(m，4H)，1.38-1.28(m，2H)，0.87(t，J＝7.2Hz，3H)； ¹³C?NMR(CDCl ₃)δ164.3，145.5，136.0，128.7，123.8，122.8，122.8，117.1，115.2，67.7，55.7，55.6，54.9，39.7，36.1，29.2，28.4，24.8，23.2，13.8。

[0240] to the pure compound that is dissolved in ether (4mL) (0.070g, add in 0.21mmol) oxalic acid be dissolved in ether (2mL) (0.020g, 0.22mmol).Filter the crystal that forms,, obtain the oxalates (0.087g, 97%) of title compound with the ether washing; HPLC-MS (ammonium acetate) [M+H] ⁺=329.3.

4-[3-(3-butylidene-8-aza-bicyclo [3.2.1] octyl group-8)-propyl group-4H-benzo [1,4] oxazine-3-ketone (81MF24)

[0241] according to GP12 mixing 4-(3-chloropropyl)-4H-benzo [1,4] oxazine-3-ketone (81MF08) (and 0.030g, 0.13mmol), K ₂CO ₃(0.037g, 0.26mmol), NaI (0.040g, 0.27mmol) and 3-butylidene-8-azabicyclo [3.2.1] octane (0.029g, 0.17mmol).Preparation property TLC (SiO ₂CH ₂Cl ₂/ MeOH 10: 1) purification obtains title compound (81MF24) (0.019g, 41%). ¹H?NMR(CDCl ₃)δ7.22-7.19(m，1H)，7.05-6.96(m，3H)，5.24(t，J＝7.2Hz，1H)，5.08(s，2H)，4.06(t，J＝6.4Hz，2H)，2.61(t，J＝6.8Hz，2H)，2.30(s，2H)，2.03-1.83(m，7H)，1.58-1.43(m，2H)，1.39-1.22(m，3H)，0.89(m，3H)； ¹³C?NMR(CDCl ₃)δ164.5，145.5，131.4，128.7，127.9，124.0，123.0，117.1，115.5，67.8，60.4，60.2，48.8，41.0，39.6，33.7，29.5，26.8，26.4，25.8，23.2，13.9。

[0242] to the pure compound that is dissolved in ether (2mL) (0.019g, add in 0.05mmol) oxalic acid be dissolved in ether (1mL) (0.005g, 0.006mmol).Filter the crystal that forms,, obtain the oxalates (0.012g, 50%) of title compound with the ether washing; HPLC-MS (ammonium acetate) [M+H] ⁺=355.3.

4-[3-(propyl group of 4-butyl piperidine base-1-)]-6-methoxyl group-4H-benzo [1,4] oxazine-3-ketone (81MF2249)

[0243] according to GP12 mixing 4-(3-chloropropyl)-6-methoxyl group-4H-benzo [1,4] oxazine-3-ketone (81MF2249b) (and 0.127g, 0.50mmol), K ₂CO ₃(0.137g, 1.0mmol), NaI (0.149g, 1.0mmol) and the 4-butyl piperidine (0.075g, 0.52mmol).CC (SiO ₂Heptane/EtOAc 4: 1-4) purification obtains title compound (81MF2249) (0.14g, 85%). ¹H?NMR(CHCl ₃)δ6.88(d，J＝8.8Hz，1H)，6.67(d，J＝2.4Hz，1H)，6.49(dd，J＝8.8Hz，J＝2.4Hz，1H)，4.51(s，2H)，3.93(t，7.2Hz，2H)，3.77(s，3H)，2.86(d，J＝10.8Hz，2H)，2.36(t，J＝7.2Hz，2H)，1.90-1.80(m，4H)，1.64(d?J＝8.8Hz，2H)，1.29-1.17(m，9H)，0.88(t，J＝6.2Hz，3H)； ¹³C?NMR(CHCl ₃)δ168.8，155.6，139.6，129.7，117.2，107.2，102.9，68.0，56.1，56.0，54.4，39.9，36.5，35.9，32.6，29.2，24.9，23.0，14.2。

[0244] to the pure compound that is dissolved in ether (4mL) (0.14g, add in 0.37mmol) oxalic acid be dissolved in ether (2mL) (0.037g, 0.41mmol).Filter the crystal that forms,, obtain the oxalates (0.15g, 90%) of title compound with the ether washing.HPLC-MS (ammonium acetate) [M+H] ⁺=361.3.

Universal method 13 (GP13)

[0245] in the 7mL bottle, adds 4-(3-chloropropyl)-4H-benzo [1,4] oxazine-3-ketone (1.0 equivalent), the K that is dissolved among the dried MeCN of 5mL ₂CO ₃(2.0 equivalent), NaI (2.0 equivalent) and 4-butyl piperidine (1.05 equivalent), and shake 48h at 60 ℃.Reactant mixture is evaporated to dried, uses 10mLH ₂CH is used in the O dilution ₂Cl ₂(3 * 13mL) extractions are filtered with PTFF Whatman filter.Merge organic layer, be evaporated to dried, with CC (heptane/EtOAc or CH ₂Cl ₂/ MeOH) or preparation property TLC (heptane/EtOAc or CH ₂Cl ₂/ MeOH) purification.

4-[3-(propyl group of 4-butyl piperidine base-1-)]-6,8-two chloro-7-ethyls-4H-benzo [1,4] oxazine-3-ketone (95MF60)

[0246] mix 6 according to GP13, and 8-two chloro-4-(3-chloro-propyl group)-7-ethyl-4H-benzo [1,4] oxazine-3-ketone ((95MF52 (2226)) (0.30g, 0.93mmol), K ₂CO ₃(0.26g, 1.86mmol), NaI (0.28g, 1.86mmol) and the 4-butyl piperidine (0.14g, 0.98mmol).CC (SiO ₂CH ₂Cl ₂/ MeOH 10: 0.2-4) purification obtains title compound (95MF60) (0.24g, 59%). ¹HNMR (CDCl ₃) δ 7.10 (and s, 1H), 4.65 (s, 2H), 3.93 (t, J=6.8Hz, 2H), 2.95-2.81 (m, 4H), 2.33 (t, J=6.8Hz, 2H), 1.90-1.78 (m, 4H), 1.66 (d, J=10.0Hz, 2H) 1.30-1.13 (m, 12H), 0.88 (s, 3H); ¹³C NMR (CDCl ₃) δ 163.5,140.6,135.3,128.2,127.7,123.2,114.3,67.9,55.8,54.4,40.1,36.4,36.0,32.7,29.2,24.8,24.6,23.1,14.2,12.7; HPLC-MS (ammonium acetate) [M+H] ⁺=427.2.

4-[3-(propyl group of 4-butyl piperidine base-1-)]-8-fluoro-4H-benzo [1,4] oxazine-3-ketone (95MF59)

[0247] according to GP13 mixing 4-(3-chloropropyl)-8-fluoro-4H-benzo [1,4] oxazine-3-ketone (95MF51 (2085)) (and 0.25g, 1.04mmol), K ₂CO ₃(0.29g, 2.1mmol), NaI (0.31g, 2.1mmol) and the 4-butyl piperidine (0.15g, 1.1mmol).CC (SiO ₂CH ₂Cl ₂/ MeOH 10: 0.2-4) purification obtains title compound (95MF59) (0.29g, 80%). ¹H?NMR(CHCl ₃)δ6.92-6.84(m，2H)，6.79-6.74(m，1H)，4.59(s，2H)，3.93(t，J＝7.4Hz，2H)，2.81(d，J＝10.8Hz，2H)，2.31(t，J＝7.0Hz，2H)，1.87-1.75(m，4H)，1.62(d，J＝9.2Hz，2H)，1.27-1.12(m，9H)，0.84(t，J＝6.8Hz，3H)； ¹³C?NMR(CDCl ₃)δ163.7，151.8(d，J＝246.0Hz)，133.8(d，J＝14.6Hz)，130.7(d，J＝3.5Hz)，122.1(d，J＝8.0Hz)，111.2(d，J＝18.4Hz)，110.4(d，J＝3.4Hz)，67.6，55.8，54.2，40.0，36.4，35.8，32.6，29.0，24.8，22.9，14.1。

[0248] to the pure compound that is dissolved in ether (4mL) (0.29g, add in 0.83mmol) oxalic acid be dissolved in ether (2mL) (0.078g, 0.86mmol).Filter the crystal that forms,, obtain the oxalates (0.31g, 85%) of title compound with the ether washing.HPLC-MS (ammonium acetate) [M+H] ⁺=349.3.

6-bromo-4-[3-(propyl group of 4-butyl piperidine base-1-)]-8-fluoro-4H-benzo [1,4] oxazine-3-ketone (95MF58)

[0249] according to GP13 mixing 6-bromo-4-(3-chloropropyl)-8-fluoro-4H-benzo [1,4] oxazine-3-ketone (95MF50 (2084)) (and 0.086g, 0.27mmol), K ₂CO ₃(0.074g, 0.53mmol), NaI (0.080g, 0.53mmol) and the 4-butyl piperidine (0.039g, 0.28mmol).CC (SiO ₂CH ₂Cl ₂/ MeOH10: 0.2-4) purification obtains title compound (95MF58) (0.040g, 35%). ¹H?NMR(CDCl ₃)δ6.92-6.84(m，2H)，6.79-6.74(m，1H)，4.59(s，2H)，3.93(t，J＝7.4Hz，2H)，2.81(d，J＝10.8Hz，2H)，2.31(t，J＝7.0Hz，2H)，1.87-1.75(m，4H)，1.62(d，J＝9.2Hz，2H)，1.27-1.12(m，9H)，0.84(t，J＝6.8Hz，3H)； ¹³C?NMR(CHCl ₃)δ163.7，151.8(d，J＝246.0Hz)，133.8(d，J＝14.6Hz)，130.7(d，J＝3.5Hz)，122.1(d，J＝8.0Hz)，111.2(d，J＝18.4Hz)，110.4(d，J＝3.4Hz)，67.6，55.8，54.2，40.0，36.4，35.8，32.6，29.0，24.8，22.9，14.1。

[0250] to the pure compound that is dissolved in ether (4mL) (0.040g, add in 0.09mmol) oxalic acid be dissolved in ether (2mL) (0.009g, 0.098mmol).Filter the crystal that forms,, obtain the oxalates (0.040g, 82%) of title compound with the ether washing.HPLC-MS (ammonium acetate) [M+H] ⁺=427.2.

4-[3-(propyl group of 4-butyl piperidine base-1-)]-8-isopropyl-4H-benzo [1,4] oxazine-3-ketone (111MF02)

[0251] according to GP13 mixing 4-(3-chloropropyl)-8-isopropyl-4H-benzo [1,4] oxazine-3-ketone (95MF98) (and 0.112g, 0.42mmol), K ₂CO ₃(0.115g, 0.84mmol), NaI (0.125g, 0.84mmol) and the 4-butyl piperidine (0.062g, 0.44mmol).Preparation property TLC (SiO ₂CH ₂Cl ₂/ MeOH 10: 1) purification obtains title compound (111MF02) (0.06g, 39%). ¹HNMR(CHCl ₃)δ6.99-6.91(m，3H)，4.55(s，2H)，3.96(t，J＝7.4Hz，2H)，3.27(m，1H)，2.89(d，J＝11.2Hz，2H)，2.40(t，J＝7.2Hz，2H)，1.93-1.83(m，4H)，1.66(d，J＝9.6Hz，2H)；1.27-1.20(m，15H)，0.88(t，J＝6.8Hz，3H)； ¹³C?NMR(CHCl ₃)δ164.7，142.9，137.5，128.7，122.6，121.1，112.9，67.7，56.0，54.2，39.9，36.4，35.9，32.5，29.1，27.2，24.9，23.0，22.7，14.2。

[0252] to the pure compound that is dissolved in ether (4mL) (0.06g, add in 0.16mmol) oxalic acid be dissolved in ether (2mL) (0.016g, 0.18mmol).Filter the crystal that forms,, obtain the oxalates (0.07g, 88%) of title compound with the ether washing.HPLC-MS (ammonium acetate) [M+H] ⁺=373.3.

(R, S)-4-[3-(4-butyl piperidine base-1)-2-hydroxyl-propyl group]-6-methyl-4H-benzo [1,4] oxazine-3-ketone (101IS86)

[0253] in dried 4mL bottle, add (R, S)-6-methyl-4-oxiranylmethyl radical-4H-benzo [1,4] oxazine-3-ketone (0.090g, 0.41mmol), the 4-butyl piperidine (0.090g, 0.60mmol), K ₂CO ₃(0.097g is 0.70mmol) with dried THF (2mL).Shake mixture 74h under 40 ℃, concentrating under reduced pressure then, residue are with EtOAc (20mL) dilution, and Na is used in water (10mL), salt water washing ₂SO ₄Dry.Filter concentrating under reduced pressure, residue flash chromatography (SiO ₂CH ₂Cl ₂/ acetone/MeOH85: 10: 5) purification obtains buttery title product (0.080g, 54%). ¹H?NMR(CD ₃OD)δ7.12(s，1H)，6.85(d，J＝8.2Hz，1H)，6.81(brd，J＝8.2Hz，1H)，4.53(ABq，14.8，18.0Hz，2H)，4.12-4.02(m，2H)，3.95-3.85(m，1H)，3.05-2.98(m，1H)，2.92-2.84(m，1H)，2.48-2.40(m，2H)，2.31(s，3H)，2.10-1.98(m，2H)，1.71-1.62(m，2H)，1.35-1.15(m，9H)，0.90(t，J＝6.8Hz)； ¹³C?NMR(CD ₃OD)δ166.0，143.7，132.4，128.8，124.4，116.5，116.4，67.5，65.9，62.8，54.6，54.5，46.1，36.3，35.6，32.2(br)，29.0，22.8，20.0，13.3。

[0254] product is dissolved in ether, adds the oxalic acid (1.1 equivalent) that is dissolved in ether.Filter the crystal that forms, use washing with acetone, obtain the oxalates (0.033g) of title compound.HPLC-MS (ammonium acetate) [M+H] ⁺=361.3.

(R, S)-4-[3-(4-butyl piperidine base-1)-2-hydroxypropyl]-4H-benzo [1,4] oxazine-3-ketone (101IS85)

[0255] will be dissolved in the chloropropylene oxide of doing DMF (7mL) (0.48g, 5.2mmol), Cs ₂CO ₃(2.3g, 7.0mmol), [(0.52g 3.5mmol) stirs 22h to 1,4] oxazine-3-ketone to the 4H-benzo.Use ether (50mL) diluted mixture thing subsequently, water (10mL) and saline (10mL) washing.Use Na ₂SO ₄Dry organic facies is filtered, concentrating under reduced pressure, residue flash chromatography (SiO ₂CH ₂Cl ₂/ acetone/MeOH 95: 3: 2) purification.The grease that obtains (0.50g 2.5mmol) is dissolved among the THF, add the 4-butyl piperidine (0.43g, 3.0mmol) and K ₂CO ₃(0.83g 6.0mmol), is reflected under 40 ℃ and shakes 72h.Concentrating under reduced pressure reaction subsequently, residue is with quick CC (SiO ₂CH ₂Cl ₂/ acetone/MeOH 85: 10: 5) purification obtains title compound (0.43g, 1.2mmol, 35%). ¹H?NMR(CD ₃OD)δ7.32(brd，J＝7.2Hz，1H)，7.06-6.94(m，3H)，4.58(ABq，J＝14.8，17.6Hz，2H)，4.13-4.03(m，2H)，3.91(dd，J＝8.8，15.2Hz)，3.97(brd，J＝10.7Hz，1H)，2.87(brd，J＝10.1Hz)，2.43(d，J＝6Hz，2H)，2.09-1.96(m，2H)，1.69-1.60(m，2H)，1.34-1.16(m，9H)，0.90(t，J＝6.8Hz)； ¹³C?NMR(CD ₃OD)δ165.8，145.8，129.2，124.0，122.6，116.7，116.2，67.4，65.9，54.7，54.5，46.2，36.3，35.6，32.2(br)，29.0，22.8，13.3。

[0256] product is dissolved in ether, adds the oxalic acid (1.1 equivalent) that is dissolved in ether.Filter the crystal that forms, use washing with acetone, obtain the oxalates (0.037g) of title compound.HPLC-MS (ammonium acetate) [M+H] ⁺=347.3.

(-)-4-[3-(4-butyl piperidine base-1)-2-hydroxypropyl]-4H-benzo [1,4] oxazine-3-ketone (101IS95)

[0257] according to top at (R/S)-4-[3-(4-butyl piperidine base-1)-2-hydroxypropyl]-[method of 1,4] oxazine-3-ketone uses (R)-(-)-chloropropylene oxide (97%) (replacing the raceme chloropropylene oxide) to obtain title compound to the 4H-benzo.Analyze (Chiralpak AD, 250 * 4.6,5 μ M by HPLC; Hexane/i-PrOH/ diethylamine 95: 4.7: 0.3,0.5mL/min) measuring its optical purity is 96.3%.

([α] _D ²⁰＝-6，c＝0.5，EtOH)。

¹H NMR, ¹³C NMR and HPLC-MS spectroscopic data are identical with racemic compound.

(R, S)-4-[3-(4-butyl piperidine)-2-methoxy-propyl]-4H-benzo [1,4] oxazine-3-ketone (101IS91)

[0258] in dried 4mL bottle, adds NaH (6.5mg, 0.15mmol), add then and be dissolved in (the R that does among the THF (1mL), S)-4-[3-(4-butyl piperidine base-1)-2-hydroxypropyl]-4H-benzo [1,4] oxazine-3-ketone (101IS85) (0.043g, 0.12mmol) solution, 2h at room temperature stirs the mixture.Add then pure MeI (7.5 μ l, 0.12mmol), at room temperature react 2h again after, reactant mixture water (2mL) quencher, with EtOAc (3 * 10mL) extraction.Use Na ₂SO ₄Dry organic facies is filtered, concentrating under reduced pressure, residue flash chromatography (SiO ₂CH ₂Cl ₂/ acetone/MeOH 90: 6: 4) purification obtains buttery title compound (5.1mg, 12%). ¹H NMR (CD ₃OD) δ 7.25 (dm, J=7.2Hz, 1H), 7.00-6.88 (m, 3H), 4.49 (ABq, J=15.2,18.8Hz, 2H), 4.06-3.94 (m, 2H), 3.69-3.61 (m, 1H), 3.25 (s, 3H), 2.94-2.82 (m, 2H), 2.54-2.36 (m, 2H), 2.10-1.94 (m, 2H), 1.64-1.55 (m, 2H), 1.25-1.05 (m, 9H), 0.81 (t, J=6.8Hz); ¹³CNMR (CD ₃OD) δ 165.9,146.0, and 129.1,124.2,122.7,116.8,116.1,76.0,67.5,60.2,57.2,54.6,54.5,43.7,36.2,35.3,31.8,28.9,22.8,13.2; HPLC-MS (ammonium acetate) [M+H] ⁺=361.3.

(R, S)-4-[2-hydroxyl-3-(3-amyl group dicyclo [3.2.1] octyl group-8)-propyl group]-4H-benzo [1,4] oxazine-3-ketone (123IS03)

[0259] will be dissolved in the chloropropylene oxide of doing DMF (7mL) (0.48g, 5.2mmol), Cs ₂CO ₃(2.3g, 7.0mmol), [(0.52g 3.5mmol) stirs 22h to 1,4] oxazine-3-ketone to the 4H-benzo.Use ether (50mL) diluted mixture thing subsequently, water (10mL) and saline (10mL) washing.Use Na ₂SO ₄Dry organic facies is filtered, concentrating under reduced pressure, and residue is with quick CC (SiO ₂CH ₂Cl ₂/ acetone/MeOH 95: 3: 2) purification.The grease that obtains (0.060g 0.29mmol) is dissolved in DMF (1.5mL), add 3-amyl group-8-azabicyclo [3.2.1] octane (0.060g, 0.33mmol) and Cs ₂CO ₃(0.30g, 0.81mmol), mixture shakes 72h under 65 ℃.Then mixture is poured in the ether (25mL), water (10mL) washing, water extracts with ether (20mL).Merge organic facies,, use Na with saline (10mL) washing ₂SO ₄Drying is filtered, concentrating under reduced pressure, residue cation exchange CC purification, quick then CC (SiO ₂CH ₂Cl ₂: purification acetone: MeOH 85/10/5) obtains title compound (0.060g, 33% (press 4H-benzo [1,4] oxazine-3-ketone meter)). ¹H?NMR(CHCl ₃)δ7.42(dm，J＝7.2Hz，1H)，7.05-6.94(m，3H)，4.60(ABq，J＝14.8，16.8Hz，2H)，4.15(dd，J＝3.2，14.0Hz，1H)，3.86-3.78(m，3H)，3.14(m，2H)，2.54(dd，J＝4.8，12.5Hz，1H)，2.22(dd，J＝9.2，12.4Hz)，2.16-1.98(m，2H)，1.98-1.83(m，2H)，1.72-1.55(m，3H)，1.43-1.34(m，2H)，1.42-1.15(m，8H)，0.87(t，J＝7.2Hz)。 ¹³C?NMR(CDCl ₃)δ165.3，145.5，129.7，124.2，122.9，117.0，116.6，67.9，67.4，60.9，58.6，56.7，46.7，38.3，36.7，36.5，28.5，28.3，28.2，27.1，22.9，14.3。HPLC-MS (ammonium acetate) [M+H] ⁺=387.3.

4-[2-(4-butyl piperidine base-1-methyl) pi-allyl]-4H-benzo [1,4 oxazine-3-ketone (123IS02)

[0260] with 3-chloro-2-chloromethyl-1-propylene (0.20g, 1.5mmol), the 4H-benzo [1,4] oxazine-3-ketone (0.15g, 1.0mmol) and Cs ₂CO ₃(0.65g 2.0mmol) is blended among the 1mL DMF, and shakes 5h under 65 ℃.With ether (20mL) diluted mixture thing, water (20mL) washing, water extracts with ether (20mL).Merge organic facies,, use Na with saline (10mL) washing ₂SO ₄Drying is filtered, concentrating under reduced pressure, and residue is with quick CC (SiO ₂Heptane/EtOAc 70: 30) purification.Product (0.080g 0.34mmol) is dissolved among the DMF (1mL), add subsequently the 4-butyl piperidine (0.053g, 0.37mmol) and Cs ₂CO ₃(0.23g, 0.71mmol), mixture shakes 24h under 65 ℃.Then mixture is poured in the ether (25mL), water (10mL) washing, water extracts with ether (20mL).Merge organic facies,, use Na with saline (10mL) washing ₂SO ₄Drying is filtered, concentrating under reduced pressure, residue cation exchange CC purification, quick then CC (SiO ₂EtOAc/MeOH/NH ₄OH (has 25%NH in the water ₃) 97.5: 2: 0.5) purification, obtain title compound (0.075g, 21%). ¹H NMR (CHCl ₃) δ 7.05-2.92 (m, 4H), 5.01 (brs, 1H), 4.82 (brs, 1H), 4.64 (brs 2H), 4.57 (brs, 2H), 2.94 (brs, 2H), 2.86 (brd, J=10.4Hz, 2H), 1.93-1.82 (m, 2H), 1.71-1.62 (m, 2H), 1.34-1.15 (m, 9H), 0.89 (t, J=6.2Hz, 3H); ¹³C NMR (CHCl ₃) δ 1.64.5,145.4,129.2,123.9,122.8,116.9,113.2,67.9,63.2,54.4,44.8,36.6,36.0,32.8,29.3,23.1,14.3; HPLC-MS (ammonium acetate) [M+H] ⁺=343.3.

(R, S)-4-[3-(4-butyl piperidine base-1)-2-fluoropropyl]-4H-benzo [1,4] oxazine-3-ketone (101IS96)

[0261] in the 4mL bottle, add (R, S)-4-butyl-1-(3-chloro-2-fluoropropyl) piperidines (0.020g, 85 μ mol), 4H-benzo [1,4] oxazine-3-ketone (0.023g 0.16mmol) and CH ₃CN (1mL).Mixture stirs 70h down at 60 ℃, with MeOH diluted mixture thing, with placing the young waiter in a wineshop or an inn's oxide liner on the cation CC to filter.Concentrating under reduced pressure obtains grease, through flash chromatography (SiO ₂Heptane: EtOAc 50/50) purification obtains buttery title compound (0.011g, 38%). ¹HNMR(CD ₃OD)δ7.28-7.24(m，1H)，7.07-6.96(m，3H)，5.05(dm，J＝50.4Hz)，(ABq，J＝15.2，20.0Hz)，4.29-4.12(m，2H)，3.00-2.92(m，2H)，2.78-2.60(m，2H)，2.14-2.05(m，2H)，1.73-1.63(m，2H)，1.35-1.16(m，10H)，0.90(t，J＝6.8Hz，3H)。 ¹³C?NMR(CD ₃OD)δ165.8，145.8，129.0，124.2，122.7，116.8，117.0，116.8，89.5(d，J＝174Hz)，67.4，60.1(d，J＝21Hz)，54.5，43.8(d，J＝23Hz)，36.2，35.4，32.0，31.9，28.9，22.8，13.2。

[0262] product is dissolved in ether, adds the oxalic acid (1.1 equivalent) that is dissolved in ether.Filter the crystal that forms, use washing with acetone, obtain the oxalates (0.037g) of title compound.HPLC-MS (ammonium acetate) [M+H] ⁺=349.3.

(S)-4-[3-(4-butyl-piperidyl-1)-2-methyl-propyl group-4H-benzo [1,4] oxazine-3-ketone (108LM53-50)

[0263] in the 4ml bottle, adds (R)-4-(3-iodo-2-methyl-propyl group)-4H-benzo [1 that is dissolved among the dried MeCN (1/2mL), the crude product (0.312g) of 4] oxazine-3-ketone (108LM46-43) and 4-butyl-piperidines (0.210g, 1.49mmol), and under 60 ℃, shook 3 days.Reactant mixture water (1ml) quencher, (2 * 1ml) extract product with EtOAc.Merge organic layer, and install on the cation exchange.Pillar with the 8% ammonium hydroxide eluting pillar that is dissolved in MeOH (2 times of column volumes), obtains product then with MeOH (2 times of column volumes) washing.Product is with quick CC (SiO ₂MeOH/DCM 1: 20) purification obtains title compound (108LM53-50) (0.193g, 17%-3 step). ¹H NMR (CHCl ₃) δ 7.18 (d, J=7.8Hz, 1H), 7.03-6.96 (m, 3H), 4.58 (ABq, J=14.3Hz, J=33.9Hz, CH ₂), 4.05-3.90 (m, 2H), 2.88 (bd, J=10.4Hz, 1H), 2.71 (bd, J=10.4Hz, 1H), 2.25-2.01 (m, 3H), 2.00-1.92 (m, 1H), 1.83-1.75 (m, 1H), and 1.68-1.56 (m, 2H), 1.33-1.12 (m, 9H), 0.95-0.85 (m, 6H); ¹³C NMR (CHCl ₃) δ 164.9,145.7,128.9,123.8,122.7,117.2,115.8,67.8,64.2,55.8,54.4,45.4,36.6,36.1,33.0,32.8,29.3,23.2,17.1,14.4; HPLC-MS (ammonium acetate) [M+H] ⁺=345.3.

(R)-4-[3-(4-butyl piperidine base-1)-2-methyl-propyl]-4H-benzo [1,4] oxazine-3-ketone (108LM22-20)

[0264] makes chemical compound (S)-4-(3-iodo-2-methyl-propyl group)-4H-benzo [1 that is dissolved among the MeCN (1/2mL) according to GP10,4] oxazine-3-ketone (108LM27-24) (0.063g, 0.19mmol) and 4-butyl-piperidines (0.053g, 0.38mmol) reaction, and under 50 ℃, shook 1 day, under 70 ℃, shook 2 days.With cation exchange CC and quick CC (SiO ₂MeOH/DCM 1: 50) purification obtains title compound (108LM22-20) (0.051g, 79%). ¹H NMR (CDCl ₃) δ 7.18-7.15 (m, 1H), 7.02-6.96 (m, 3H), 4.60 (ABq, J=15.0Hz, J=31.3Hz, CH ₂), 3.99 (dd, J=8.1Hz, 13.8Hz, 1H), 3.92 (dd, J=5.0Hz, 13.8Hz, 1H), 2.88 (bd, J=10.0Hz, 1H), 2.72 (bd, J=10.0Hz, 1H), 2.26-2.02 (m, 3H), 2.00-1.92 (m, 1H), 1.85-1.75 (m, 1H), 1.70-1.59 (m, 2H), 1.32-1.14 (m, 9H), 0.92-0.85 (m, 6H); HPLC-MS (ammonium acetate) [M+H] ⁺=345.3.

Universal method 14 (GP14)

[0265] in the 4mL bottle, adds corresponding heterocyclic compound (1 equivalent) and corresponding piperidines (1.1 equivalent), and under 60 ℃, shook 2 days.Add Et ₃N (1/2mL) continued to shake 1 day.Reactant mixture water (1mL) quencher adds Et ₂O (1mL) and sodium hydroxide (is 10 up to pH).Product Et ₂O (2 * 1mL) extractions.Merge organic layer, use Na ₂SO ₄Drying concentrates.Product is used quick CC (SiO then with cation exchange CC purification ₂MeOH/DCM 1: 50) purification.

(R)-4-[2-methyl-3-(4-propoxyl group piperidyl-1)-propyl group]-4H-benzo [1,4] oxazine-3-ketone (108LM32-29)

[0266] makes chemical compound (S)-4-(3-iodo-2-methyl-propyl group)-4H-benzo [1 that is dissolved among the MeCN (1/2mL) according to GP14,4] oxazine-3-ketone (108LM27-24) (0.202g, 0.61mmol) and 4-propoxyl group-piperidines (79KS66) (0.097g, 0.67mmol) reaction, obtain title compound (108LM32-29) (0.136g, 65%). ¹H NMR (CHCl ₃) δ 7.15 (bd, J=7.3Hz, 1H), 7.03-6.95 (m, 3H), 4.60 (ABq, J=13.9Hz, J=31.6Hz, CH ₂), 4.05-3.90 (m, 2H), 3.48 (t, J=7.0Hz, CH ₂), 3.28-3.20 (m, 1H), 2.79 (bs, 1H), 2.63 (bs, 1H), 2.27-2.11 (m, 3H), 2.10-1.93 (m, 2H), 1.92-1.83 (m, 2H), 1.63-1.52 (m, 4H), 0.94-0.86 (m, 6H); ¹³C NMR (CHCl ₃) δ 164.5,145.4,128.5,123.4,122.3,116.9,115.2,75.0,69.4,67.4,63.2,52.5,51.5,45.0,31.6,31.5,29.1,23.1,16.6,10.5; HPLC-MS (ammonium acetate) [M+H] ⁺=347.3.

(R)-4-[3-(4-butylidene piperidyl-1)-2-methyl-propyl]-4H-benzo [1,4] oxazine-3-ketone (108LM33-30)

Make chemical compound (S)-4-(3-iodo-2-methyl-propyl group)-4H-benzo [1 that is dissolved among the MeCN (1/2mL) according to GP14,4] oxazine-3-ketone (108LM27-24) (0.441g, 1.33mmol) and 4-butylidene piperidines (111MF05) (0.204g, 1.47mmol) reaction, obtain title compound (108LM33-30) (0.293g, 64%). ¹H NMR (CDCl ₃) δ 7.19 (bd, J=7.0Hz, 1H), 7.04-6.97 (m, 3H), 5.13 (t, J=7.9Hz, CH), 4.60 (ABq, J=14.1Hz, J=16.2Hz, CH ₂), 4.00 (d, J=7.0Hz, CH ₂), 2.50-2.38 (m, 2H), 2.35-2.05 (m, 9H), 1.95 (dt, J=7.0Hz, CH ₂), 1.50-1.40 (m, 2H), 0.94-0.86 (m, 6H); ¹³C NMR (CHCl ₃) δ 165.0,145.8,136.3,128.9,123.8,122.8,122.7,117.3,115.7,67.9,63.7,56.5,55.7,45.5,36.4,29.4,28.6,23.4,17.1,13.9; HPLC-MS (ammonium acetate) [M+H] ⁺=343.3.

Universal method 15 (GP15)

[0267] adding is dissolved in Et in the 7mL bottle ₃Corresponding heterocyclic compound among the N (1/2mL) (1 equivalent) and corresponding piperidines (1.1 equivalent), and under 60 ℃, shook 4 days.Reactant mixture water (1mL) quencher adds Et ₂O (1mL) and sodium hydroxide (is 10 up to pH).Product Et ₂O (10 * 1mL) and EtOAc (10 * 1mL) extraction.Merge organic layer, dry (Na ₂SO ₄), concentrate.Product is used quick CC (SiO then with cation exchange CC purification ₂MeOH/DCM 1: 20) purification.

(R)-4-[3-(3-butyl-8-aza-bicyclo [3.2.1] octyl group-8]-2-methyl-propyl-4H-benzo [1,4] oxazine -3-ketone (108LM38-35)

[0268] makes according to GP15 and be dissolved in Et ₃Chemical compound (S)-4-among the N (1/2mL) (3-iodo-2-methyl-propyl)-4H-benzo [1,4] oxazine-3-ketone (108LM27-24) (0.092g, 0.28mmol) and 3-butyl-8-aza-bicyclo [3.2.1] octane (104KS29) (0.051g, 0.31mmol) reaction, obtain title compound (108LM38-35) (0.068g, 64%). ¹H NMR (CHCl ₃) δ 7.32 (d, J=6.7Hz, 1H), 7.03-6.95 (m, 3H), 4.60 (ABq, J=7.2Hz, J=10.8Hz, CH ₂), 4.12-4.00 (m, 2H), 3.16 (bs, 1H), 3.07 (bs, 1H), 2.33 (dd, J=6.1Hz, J=2.1Hz, 1H), 2.12 (t, J=4.7Hz, 1H), 2.01-1.78 (m, 2H), and 1.58-1.40 (m, 5H), 1.38-1.13 (m, 9H), 0.92-0.84 (m, 6H); ¹³C NMR (CHCl ₃) δ 164.9,145.7,128.9,123.7,122.7,117.1,116.2,67.9,61.8,60.0,58.1,45.4,38.7,38.6,37.1,31.6,29.4,28.2,27.4,26.5,23.1,17.1,14.3; HPLC-MS (ammonium acetate) [M+H] ⁺=371.3.

(R)-4-[2-methyl-3-(propyl group of 3-amyl group-8-azabicyclo [3.2.1] octyl group-8-)]-4H-benzo [1,4] Evil Piperazine-3-ketone (108LM39-36)

Make according to GP15 and to be dissolved in Et ₃Chemical compound (S)-4-among the N (1/2mL) (3-iodo-2-methyl-propyl)-4H-benzo [1,4] oxazine-3-ketone (108LM27-24) (0.083g, 0.25mmol) and 3-amyl group-8-aza-bicyclo [3.2.1] octane (104KS32-2) (0.051g, 0.28mmol) reaction, obtain title compound (108LM39-36) (0.061g, 63%). ¹H NMR (CDCl ₃) δ 7.33-7.29 (m, 1H), 7.03-6.96 (m, 3H), 4.60 (ABq, J=14.8Hz, J=37.1Hz, CH ₂), 4.14-4.00 (m, 2H), 3.13 (bs, 1H), 3.05 (bs, 1H), 2.63-2.50 (m, 1H), 2.17-2.03 (m, 3H), 2.00-1.80 (m, 3H), 1.72-1.53 (m, 3H), 1.42-1.15 (m, 10H), 0.93-0.85 (m, 6H); ¹³CNMR (CHCl ₃) δ 165.0,145.7,128.9,123.7,122.6,117.1,116.1,67.9,60.9,58.9,58.2,45.3,38.4,37.0,36.8,32.2,31.7,28.5,28.3,27.2,22.9,17.1,14.3; HPLC-MS (ammonium acetate) [M+H] ⁺=385.3.

Universal method 16 (GP16)

[0269] in the 7mL bottle, adds 4-(3-iodo-2-methyl-propyl)-4H-benzo [1,4] oxazine-3-ketone (1.0 equivalent) and amine (1.0 equivalent), and under 60 ℃, shook 20 hours.In reactant mixture, add Et ₃N (2.5 equivalent), and under 60 ℃, shook 60-80 hour.Concentrated reaction mixture, and be dissolved among the 1M NaOH (10mL), CH used ₂Cl ₂(3 * 15mL) extractions are with PTFF Whatman filter drying.Merge organic layer, concentrate, with cation exchange CC and CC (heptane/EtOAc) or preparation property HPLC purification.

(R)-6-fluoro-4-[2-methyl-3-(4-propoxyl group-piperidyl-1)-propyl group]-4H-benzo [1,4] oxazine-3-ketone (108LM30-27)

[0270] makes chemical compound (S)-6-fluoro-4-(3-iodo-2-methyl-propyl group)-4H-benzo [1 that is dissolved among the MeCN (1/2mL) according to GP10,4] oxazine-3-ketone (111MF04) (0.400g, 1.15mmol) and 4-propoxyl group-piperidines (79KS66) (0.332g, 2.29mmol) reaction, and under 60 ℃, shook 3 days, under 70 ℃, shook 1 day.With cation exchange CC and quick CC (SiO ₂MeOH/DCM 1: 50 → 1: 20) purification obtains title compound (108LM30-27) (0.263g, 63%). ¹H NMR (CHCl ₃) δ 6.96 (dd, J=9.7Hz, J=2.9Hz, 1H), 6.91 (dd, J=8.9Hz, J=4.9Hz, 1H), 6.66 (dt, J=8.9Hz, J=2.9Hz, 1H), 4.56 (ABq, J=15.5Hz, J=31.7Hz, CH ₂), 3.95 (dd, J=13.5Hz, J=8.1Hz, 1H), 3.88 (dd, J=13.5Hz, J=4.7Hz, 1H), 3.38 (t, J=6.7Hz, CH ₂), 3.32-3.23 (m, 1H), 2.79 (bs, 1H), 2.62 (bs, 1H), 2.26-2.12 (m, 3H), 2.19-1.95 (m, 2H), 1.94-1.84 (m, 2H), 1.66-1.53 (m, 4H), 0.95-0.85 (m, 6H); ¹³C NMR (CHCl ₃) δ 164.9,158.5 (d, J=952.8Hz, 1H), 141.7 (d, J=9.2Hz, 1H), 130.0 (d, J=42.4Hz, 1H), 117.7 (d, J=38.4Hz, 1H), 109.6 (d, J=93.2Hz, 1H), 103.4 (d, J=114.4Hz, 1H), 75.2,69.8,67.9,63.7,52.8,52.0,45.7,31.8,31.6,29.5,23.5,17.1,10.9; HPLC-MS (ammonium acetate) [M+H] ⁺=365.3.

(R)-4-[3-(4-butylidene piperidyl-1)-2-methyl-propyl group]-6-fluoro-4H-benzo [1,4] oxazine-3-ketone (111MF06)

[0271] according to GP16 mixing cpd (S)-6-fluoro-4-(3-iodo-2 methyl-propyls)-4H-benzo [1,4] oxazine-3-ketone (111MF04) (and 0.718g, 2.06mmol) and 4-butylidene piperidines (0.301g, 2.16mmol).CC (SiO ₂Heptane/EtOAc 4: 1-4) purification obtains title compound (111MF06) (0.40g, 54%). ¹H?NMR(CHCl ₃)δ7.01(dd，J＝3.0Hz，J＝10.2Hz，1H)，6.90(dd，J＝5.4Hz，J＝8.6Hz，1H)，6.89-6.63(m，1H)，5.12(t，J＝7.4Hz，1H)，4.63-4.51(m，2H)，4.02-3.89(m，1H)，2.51-2.44(m，2H)，2.32-2.23(m，5H)，2.21-2.15(m，5H)，2.11-2.03(m，1H)，1.98-1.93(m，2H)，1.39-1.29(m，2H)，0.91-0.86(m，6H)； ¹³C?NMR(CHCl ₃)δ164.8，158.5(d，J＝239.4Hz)，141.6(d，J＝2.7Hz)，136.2，130.0(d，J＝10.8Hz)，122.7，117.6(d，J＝9.3Hz)，109.5(d，J＝23.1Hz)，103.4(d，J＝29.1Hz)，67.8，63.7，56.6，55.8，45.7，36.2，29.4，29.3，28.4，23.3，17.0，13.9。

[0272] to the pure compound that is dissolved in ether (4mL) (0.38g, add in 1.0mmol) oxalic acid be dissolved in ether (2mL) (0.104g, 1.15mmol).Filter the crystal that forms,, obtain the oxalates (0.44g, 92%) of title compound with the ether washing; HPLC-MS (ammonium acetate) [M+H] ⁺=361.4.

(R)-4-[3-(4-butyl piperidine base-1)-2-methyl-propyl]-6-fluoro-4H-benzo [1,4] oxazine-3-ketone (111MF08)

[0273] according to GP16 mixing cpd (S)-6-fluoro-4-(3-iodo-2-methyl-propyl group)-4H-benzo [1,4] oxazine-3-ketone (111MF04) (and 0.873g, 2.50mmol) and the 4-butyl piperidine (0.371g, 2.63mmol).CC (SiO ₂Heptane/EtOAc 4: 1-4) purification obtains title compound (111MF08) (0.53g, 58%). ¹H?NMR(CDCl ₃)δ7.01(d，J＝10.0Hz，1H)，6.92-6.88(m，1H)，6.68-6.64(m，1H)，5.57(q，J＝32.4Hz，J＝15.2Hz，2H)，4.02-3.83(m，2H)，2.92-2.70(m，2H)，2.23-2.10(m，2H)，2.04-1.97(m，2H)，1.81(t，J＝10.8Hz，1H)，1.72-1.61(m，2H)，1.36-1.19(m，9H)，0.90-0.88(m，6H)； ¹³C?NMR(CHCl ₃)δ164.8，158.5(d，J＝239.4Hz)，141.6(d，J＝2.3Hz)，130.0(d，J＝10.4Hz)，117.6(d，J＝9.6Hz)，109.4(d，J＝23.1Hz)，103.5(d，J＝29.3Hz)，67.8，64.1，56.0，54.3，45.7，36.5，36.0，33.0，32.5，29.5，29.2，23.1，17.1，14.3。

[0274] to the pure compound that is dissolved in ether (4mL) (0.53g, add in 1.5mmol) oxalic acid be dissolved in ether (2mL) (0.104g, 1.15mmol).Filter the crystal that forms,, obtain the oxalates (0.614g, 93%) of title compound with the ether washing; HPLC-MS (ammonium acetate) [M+H] ⁺=363.3.

(R)-4-[3-(3-butyl-8-azabicyclo [3.2.1] octyl group-8)-2-methyl-propyl]-6-fluoro-4H-benzo [1,4] Oxazine-3-ketone (111MF26)

[0275] according to GP16 mixing cpd (S)-6-fluoro-4-(3-iodo-2-methyl-propyl group)-4H-benzo [1,4] oxazine-3-ketone (111MF04) (and 0.219g, 0.6mmol) and 3-butyl-8-azabicyclo [3.2.1] octane (0.10g, 0.6mmol).CC (SiO ₂(4: 1-4) purification obtains title compound (111MF26) (0.16g, 58%) to heptane/EtOAc. ¹H?NMR(CHCl ₃)δ7.16(dd，J＝2.8Hz，J＝10.0Hz，1H)，6.90(dd，J＝5.0Hz，J＝9.0Hz，1H)，6.69-6.63(m，1H)，4.58(q，J＝14.8Hz，J＝38.0Hz，2H)，4.10-3.93(m，2H)，3.16-3.06(m，2H)，2.33(dd，J＝4.0Hz，J＝12.8Hz，1H)，2.05(t，J＝11.6Hz，1H)，1.94-1.82(m，2H)，1.58-1.43(m，6H)，1.39-1.32(m，2H)，1.31-1.15(m，6H)，0.90-0.87(m，6H)； ¹³C?NMR(CDCl ₃)δ164.9，158.5(d，J＝239.4Hz)，141.6(d，J＝2.7Hz)，130.0(d，J＝10.4Hz)，117.5(d，J＝9.3Hz)，109.4(d，J＝23.5Hz)，103.9(d，J＝28.9Hz)，67.8，61.9，60.1，58.2，45.6，38.6，38.5，36.9，31.8，29.4，28.2，27.4，26.5，23.1，17.1，14.3。

[0276] to the pure compound that is dissolved in ether (4mL) (0.16g, add in 0.41mmol) oxalic acid be dissolved in ether (2mL) (0.039g, 0.43mmol).Filter the crystal that forms,, obtain the oxalates (0.173g, 88%) of title compound with the ether washing; HPLC-MS (ammonium acetate) [M+H] ⁺=389.3.

(R)-6-fluoro-4-(2-methyl-3-(3-amyl group-8-azabicyclo [3.2.1] octyl group-8]-propyl group-4H-benzo [1,4] Oxazine-3-ketone (111MF27)

[0277] according to GP16 mixing cpd (S)-6-fluoro-4-(3-iodo-2-methyl-propyl)-4H-benzo [1,4] oxazine-3-ketone (111MF04) (and 0.208g, 0.6mmol) and 3-amyl group-8-azabicyclo [3.2.1] octane (0.10g, 0.56mmol).CC (SiO ₂Heptane/EtOAc 4: 1-4) purification obtains title compound (111MF27) (0.16g, 58%). ¹H?NMR(CDCl ₃)δ7.13(dd，J＝2.8Hz，J＝10.0Hz，1H)，6.90(dd，J＝5.2Hz，J＝8.8Hz，1H)，6.68-6.63(m，1H)，4.57(q，J＝14.8Hz，J＝40.0Hz，1H)，4.11-3.94(m，2H)，3.14-3.04(m，2H)，2.30(dd，J＝4.0Hz，J＝12.8Hz，1H)，2.20-2.09(m，2H)，2.06-2.00(m，1H)，1.95-1.82(m，3H)，1.71-1.52(m，3H)，1.40-1.34(m，2H)，1.32-1.19(m，8H)，0.89-0.85(m，6H)； ¹³C?NMR(CHCl ₃)δ164.9，158.5(d，J＝239.4Hz)，141.6(d，J＝2.6Hz)，130.0(d，J＝10.8Hz)，117.5(d，J＝9.3Hz)，109.4(d，J＝23.4Hz)，103.8(d，J＝28.9Hz)，67.8，61.0，59.0，58.2，45.5，38.4，36.6，36.5，32.8，31.8，28.4，28.4，28.2，27.2，22.8，7.0，14.2。

[0278] to the pure compound that is dissolved in ether (4mL) (0.16g, add in 0.41mmol) oxalic acid be dissolved in ether (2mL) (0.039g, 0.43mmol).Filter the crystal that forms,, obtain the oxalates (0.198g, 97%) of title compound with the ether washing; HPLC-MS (ammonium acetate) [M+H] ⁺=403.3.

(R)-4-[3-(4-butyl piperidine base-1)-2-methyl-propyl]-7-fluoro-4H-benzo [1,4] oxazine-3-ketone (112KK04)

[0279] [(0.274g, 0.78mmol) (0.226g 1.60mmol), and seals 1,4] oxazine-3-ketone (111MF20) with the 4-butyl piperidine to add (S)-7-fluoro-4-(3-iodo-2-the methyl-propyl)-4H-benzo that is dissolved among the MeCN (4mL) in the microwave bottle.Behind 100 ℃ of following microwave irradiation 60min, reactant mixture is used quick CC (SiO then with cation exchange CC purification ₂CH ₂Cl ₂/ MeOH 50: 1) purification obtains title compound (112KK04) (0.1 80g, 63%). ¹H?NMR(CD ₃OD)δ7.24-7.21(m，1H)，6.81-6.76(m，2H)，4.60(ABq，J＝17.4Hz，J＝15.1Hz，CH ₂)，3.98(dd，J＝14.3Hz，J＝5.9Hz，1H)，3.87(dd，J＝14.3Hz，J＝7.6Hz，1H)，2.86(d，J＝11.0Hz，1H)，2.73(d，J＝9.8Hz，1H)，2.28-2.23(m，1H)，2.16-2.08(m，2H)，1.93-1.81(m，2H)，1.79-1.62(m，2H)，1.32-1.13(m，9H)，0.93-0.88(m，2CH ₃)； ¹³C?NMR(CD ₃OD)δ166.1，160.3(d，J＝242.3Hz)，148.1(d，J＝11.9Hz)，126.4(d，J＝2.9Hz)，117.8(d，J＝9.4Hz)，109.9(d，J＝22.9Hz)，105.7(d，J＝26.1Hz)，68.6，65.1，56.3，55.4，46.6，37.5，37.0，33.6，33.4，30.1，29.9，24.0，17.2，14.4。

[0280] product is dissolved in MeOH/Et ₂Among the O, adding is dissolved in Et ₂Oxalic acid among the O.Filter the crystal that forms, use washing with acetone, obtain the oxalates (0.176g) of title compound.HPLC-MS (ammonium acetate) [M+H] ⁺=363.29.

(R)-7-fluoro-4-[2-methyl-3-(propyl group of 4-propoxyl group piperidyl-1-)]-4H-benzo [1,4] oxazine-3-ketone (111MF28)

[0281] according to GP16 mixing cpd (S)-7-fluoro-4-(3-iodo-2-methyl-propyl)-4H-benzo [1,4] oxazine-3-ketone (111MF20) (and 0.501g, 1.43mmol) and 4-propoxyl group piperidines (0.205g, 1.43mmol).CC (SiO ₂Heptane/EtOAc 4: 1-4) purification obtains title compound (111MF28) (0.375g, 71%). ¹H?NMR(CDCl ₃)δ7.12-7.08(m，1H)，6.74-6.69(m，2H)，4.59(q，J＝15.0Hz，J＝31.0Hz，2H)，4.01-3.88(m，2H)，3.39(t，J＝6.8Hz，2H)，3.29-3.22(m，1H)，2.77(t，J＝6.3Hz，1H)，2.63(t，J＝5.6Hz，1H)，2-26-2.12(m，3H)，2.04-1.96(m，2H)，1.88-1.84(m，2H)，1.62-1.50(m，4H)，0.93-0.87(m，6H)； ¹³C?NMR(CDCl ₃)δ164.2，158.9(d，J＝241.9Hz)，146.5(d，J＝12.1Hz)，125.2(d，J＝3.0Hz)，116.1(d，J＝9.6Hz)，109.0(d，J＝22.3Hz)，105.2(d，J＝25.8Hz)，75.2，69.8，67.8，63.5，52.8，51.8，45.5，31.9，31.8，29.4，23.5，17.0，10.8。

[0282] to the pure compound that is dissolved in ether (4mL) (0.375g, add in 1.03mmol) oxalic acid be dissolved in ether (2mL) (0.097g, 1.08mmol).Filter the crystal that forms,, obtain the oxalates (0.41g, 88%) of title compound with the ether washing; HPLC-MS (ammonium acetate) [M+H] ⁺=365.3.

(R)-4-[3-(4-butylidene piperidyl-1)-2-methyl-propyl]-7-fluoro-4H-benzo [1,4] oxazine-3-ketone (111MF29)

[0283] according to GP16 mixing cpd (S)-7-fluoro-4-(3-iodo-2-methyl-propyl)-4H-benzo [1,4] oxazine-3-ketone (111MF20) (and 0.515g, 1.47mmol) and 4-butylidene piperidines (0.205g, 1.47mmol).CC (SiO ₂Heptane/EtOAc 4: 1-4) purification obtains title compound (111MF29) (0.393g, 73%). ¹H?NMR(CDCl ₃)δ7.17-7.12(m，1H)，6.74-6.69(m，2H)，5.15-5.11(t，J＝7.2Hz，1H)，4.61(q，J＝15.2Hz，2H)，4.04-3.92(m，2H)，2.48-2.40(m，2H)，2.32-2.13(m，9H)，1.96(q，J＝7.2Hz，2H)，1.38-1.30(m，2H)，0.91-0.86(m，6H)； ¹³C?NMR(CDCl ₃)δ164.1，158.9(d，J＝243.4Hz)，146.5(d，J＝11.9Hz)，136.1，125.2(d，J＝3.0Hz)，128.9，116.2(d，J＝22.7Hz)，109.0(d，J＝22.7Hz)，105.2(d，J＝26.2Hz)，67.8，63.7，56.5，55.7，54.6，36.3，29.3，28.5，23.3，17.1，13.9。

[0284] to the pure compound that is dissolved in ether (4mL) (0.393g, add in 1.09mmol) oxalic acid be dissolved in ether (2mL) (0.103g, 1.14mmol).Filter the crystal that forms,, obtain the oxalates (0.46g, 94%) of title compound with the ether washing; HPLC-MS (ammonium acetate) [M+H] ⁺=361.3.

(R)-4-[3-(3-butyl-8-azabicyclo [3.2.1] octyl group-8)-2-methyl-propyl]-7-fluoro-4H-benzo [1,4] Oxazine-3-ketone (112KK05)

[0285] in the microwave bottle, adds adding (S)-7-fluoro-4-(3-iodo-2-the methyl-propyl)-4H-benzo [1 that is dissolved among the MeCN (2mL), 4] oxazine-3-ketone (111MF20) (0.047g, 0.13mmol) and 3-butyl-8-azabicyclo [3.2.1] octane (0.039g, 0.23mmol), and sealing.Behind 100 ℃ of following microwave irradiation 60min, reactant mixture is used quick CC (SiO then with cation exchange CC purification ₂CH ₂Cl ₂/ MeOH 50: 1) purification obtains title compound (112KK05) (0.017g, 33%). ¹HNMR(CD ₃OD)δ7.34-7.30(m，1H)，6.80-6.75(m，2H)，4.61(ABq，J＝18.8Hz，J＝15.1Hz，CH ₂)，4.04(dd，J＝14.3Hz，J＝5.9Hz，1H)，3.93(dd，J＝14.3Hz，J＝8.2Hz，1H)，3.18-3.10(m，2H)，2.36-2.23(m，2H)，2.03-1.85(m，3H)，1.62-1.45(m，5H)，1.36-1.14(m，8H)，0.92-0.87(m，2CH ₂)； ¹³C?NMR(CD ₃OD)δ166.2，160.4(d，J＝242.3Hz)，148.1(d，J＝11.9Hz)，126.3(d，J＝2.9Hz)，11?8.1(d，J＝9.7Hz)，109.8(d，J＝22.9Hz)，105.7(d，J＝26.5Hz)，68.6，62.5，61.2，58.3，46.4，39.0，37.9，32.1，30.2，29.0，27.8，27.2，23.9，17.2，14.4。

[0286] product is dissolved in MeOH/Et ₂Among the O, adding is dissolved in Et ₂Oxalic acid among the O.Filter the crystal that forms, use washing with acetone, obtain the oxalates oxalates (0.016g) of title compound.HPLC-MS (ammonium acetate) [M+H] ⁺=389.34.

(R)-7-fluoro-4-[2-methyl-3-(3-amyl group-8-azabicyclo [3.2.1] octyl group-8)-propyl group-4H-benzo [1,4] Oxazine-3-ketone (111MF30)

[0287] according to GP16 mixing cpd (S)-7-fluoro-4-(3-iodo-2-methyl-propyl)-4H-benzo [1,4] oxazine-3-ketone (111MF20) (and 0.208g, 0.59mmol) and 3-amyl group-8-azabicyclo [3.2.1] octane (0.106g, 0.58mmol).CC (SiO ₂Heptane/EtOAc 4: 1-4) with preparation property HPLC purification, obtain title compound (111MF30) (0.070g, 29%). ¹H?NMR(CDCl ₃)δ7.23-7.19(m，1H)，6.66-6.60(m，2H)，4.60-4.46(m，2H)，4.05-3.99(m，1H)，3.95-3.90(m，1H)，3.06-3.03(m，1H)，2.99-2.96(m，1H)，2.24-2.19(m，1H)，2.07-1.94(m，3H)，1.90-1.73(m，3H)，1.60-1.45(m，3H)，1.33-1.25(m，2H)，1.24-1.12(m，8H)，0.83-0.78(m，6H)； ¹³C?NMR(CDCl ₃)δ164.1，158.8(d，J＝243.3Hz)，146.4(d，J＝11.5Hz)，125.1(d，J＝3.1Hz)，116.6(d，J＝9.3Hz)，108.9(d，J＝22.8Hz)，105.0(d，J＝25.7Hz)，67.7，60.9，58.8，58.1，45.4，38.3，36.8，36.6，32.1，31.6，28.5，28.4，28.1，27.0，22.8，17.0，14.2。

[0288] to the pure compound that is dissolved in ether (1mL) (0.070g, add in 0.17mmol) oxalic acid be dissolved in ether (1mL) (0.016g, 0.18mmol).Filter the crystal that forms,, obtain the oxalates (0.082g, 96%) of title compound with the ether washing; HPLC-MS (ammonium acetate) [M+H] ⁺=402.56.

(R)-4-[3-(4-butyl piperidine base-1)-2-methyl-propyl group]-6-methoxyl group-4H-benzo [1,4] oxazine-3-ketone (111MF38)

[0289] according to GP16 mixing cpd (S)-4-(3-iodo-2-methyl-propyl)-6-methoxyl group-4H-benzo [1,4] oxazine-3-ketone (11MF36) (and 0.636g, 1.77mmol) and the 4-butyl piperidine (0.226g, 1.6mmol).CC (SiO ₂Heptane/EtOAc 4: 1-4) with preparation property HPLC purification, obtain title compound (111MF38) (0.245g, 27%). ¹H?NMR(CDCl ₃)δ6.89(d，J＝8.8Hz，1H)，6.72(d，J＝2.4Hz，1H)，6.50(dd，J＝2.8，J＝8.8Hz，1H)，4.54(q，J＝32.4，J＝14.8，2H)，3.94-3.90(m，2H)，3.77(s，3H)，2.90(d，J＝11.2Hz，1H)，2.72(d，J＝10.8Hz，1H)，2.25-2.10(m，3H)，1.93(t，J＝11.2Hz，1H)，1.80(t，J＝11.2Hz，1H)，1.61(d，J＝10.8Hz，2H)，1.31-1.19(m，9H)，0.90-0.86(m，6H)； ¹³C?NMR(CDCl ₃)δ165.3，155.5，139.7，129.8，117.2，107.1，103.3，68.0，64.2，55.9，55.7，54.5，45.5，36.5，36.0，32.9，32.5，29.2，29.2，23.1，16.9，14.3。

[0290] to the pure compound that is dissolved in ether (2mL) (0.245g, add in 0.65mmol) oxalic acid be dissolved in ether (2mL) (0.062g, 0.68mmol).Filter the crystal that forms,, obtain the oxalates (0.229g, 75%) of title compound with the ether washing; HPLC-MS (ammonium acetate) [M+H] ⁺=375.3.

(R)-4-[3-(4-butylidene piperidyl-1)-2-methyl-propyl]-6-methoxyl group-4H-benzo [1,4] oxazine-3- Ketone (111MF39)

[0291] according to GP16 mixing cpd (S)-4-(3-iodo-2-methyl-propyl)-6-methoxyl group-4H-benzo [1,4] oxazine-3-ketone (111MF36) (and 0.612g, 1.69mmol) and 4-butylidene piperidines (0.212g, 1.5mmol).CC (SiO ₂Heptane/EtOAc 4: 1-4) purification obtains title compound 111MF39) (0.489g, 77%). ¹H NMR (CDCl ₃) δ 6.90 (d, J=8.4Hz, 1H), 6.73 (d, J=2.8Hz, 1H), 6.50 (dd, J=8.4Hz, J=2.8Hz, 1H), 5.11 (t, J=7.6Hz, 1H), 4.54 (q, J=14.4Hz, 2H), 3.97-3.94 (d, J=6.8Hz, 2H), 3.78 (s, 3H), 2.48-2.41 (m, 2H), 2.33-2.23 (m, 5H), and 2.20-2.13 (m, 4H), 1.96 (q, J=7.4Hz, 2H), and 1.40-1.29 (m, 2H), 0.91-0.86 (m, 6H); ¹³C NMR (CHCl ₃) δ 165.3,155.5,139.8,136.5,129.8,122.5,117.2,107.0,103.4,68.1,63.8,56.5,56.0,55.7,45.5,36.2,29.3,29.2,28.4,23.3,16.9,13.9; HPLC-MS (ammonium acetate) [M+H] ⁺=373.3.

(R)-4-[3-(3-butyl-8-azabicyclo [3.2.1] octyl group-8)-2-methyl-propyl]-6-methoxyl group-4H-benzene And [1,4] oxazine-3-ketone (111MF40)

[0292] according to GP16 mixing cpd (S)-4-(3-iodo-2-methyl-propyl)-6-methoxyl group-4H-benzo [1,4] oxazine-3-ketone (111MF36) (and 0.239g, 0.66mmol) and 3-butyl-8-aza-bicyclo [3.2.1] octane (0.100g, 0.60mmol).CC (SiO ₂Heptane/EtOAc 4: 1-4) purification obtains title compound (111MF40) (0.163g, 61%). ¹H NMR (CDCl ₃) δ 6.88 (d, J=8.8Hz, 1H), 6.85 (d, J=2.8Hz, 1H), 6.49 (dd, J=8.8Hz, J=2.8Hz, 1H), 4.61-4.47 (m, 2H), 4.01-3.99 (m, 2H), 3.77 (s, 3H), 3.17-3.04 (m, 2H), 2.35-2.29 (m, 1H), 2.14-1.79 (m, 3H), 1.57-1.13 (m, 6H), 0.88 (m, 3H); ¹³C NMR (CDCl ₃) δ 165.4,155.6,139.8,129.8,117.1,107.0,103.8,68.0,61.6,60.2,58.1,56.0,45.4,38.5,38.4,36.9,31.6,29.4,28.2,27.3,26.5,23.9,14.3; HPLC-MS (ammonium acetate) [M+H] ⁺=401.3.

(R)-6-methoxyl group-4-[2-methyl-3-(propyl group of 3-amyl group-8-aza-bicyclo [3.2.1] octyl group-8-)]-4H-benzene And [1,4] oxazine-3-ketone (111MF41)

[0293] according to GP16 mixing cpd (S)-4-(3-iodo-2-methyl-propyl)-6-methoxyl group-4H-benzo [1,4] oxazine-3-ketone (111MF36) (and 0.226g, 0.63mmol) and 3-amyl group-8-azabicyclo [3.2.1] octane (0.101g, 0.56mmol).CC (SiO ₂Heptane/EtOAc 4: 1-4) with preparation property HPLC purification, obtain title compound (111MF41) (0.101g, 39%). ¹H NMR (CHCl ₃) δ 6.89 (d, J=8.8Hz, 1H), 6.81 (d, J=2.8Hz, 1H), 6.49 (dd, J=8.8Hz, J=2.8Hz, 1H), 4.60-4.46 (m, 2H), 4.01 (d, J=6.8Hz, 2H), 3.77 (s, 3H), 3.15-3.02 (m, 2H), 2.32-2.26 (m, 1H), 2.20-1.79 (m; 7H), and 1.68-1.51 (m, 3H), 1.42-1.16 (m, 10H), 0.89-0.85 (m, 6H); ¹³C NMR (CDCl ₃) δ 168.4,155.6,139.8,129.8,117.0,106.9,103.8,68.0,60.6,59.1,58.1,56.0,45.3,39.4,36.6,36.4,32.2,31.5,28.4,28.4,28.0,27.3,22.8,16.8,14.2; HPLC-MS (ammonium acetate) [M+H] ⁺=415.3.

(R)-6-methoxyl group-4-[2-methyl-3-(propyl group of 4-propoxyl group piperidyl-1-)]-4H-benzo [1,4] oxazine-3- Ketone (111MF42)

[0294] according to GP16 mixing cpd (S)-4-(3-iodo-2-methyl-propyl)-6-methoxyl group-4H-benzo [1,4] oxazine-3-ketone (111MF36) (and 0.556g, 1.5mmol) and 4-propoxyl group piperidines (0.20g, 1.4mmol).CC (SiO ₂Heptane/EtOAc 4: 1-4) purification obtains title compound (111MF42) (0.30g, 53%). ¹H NMR (CDCl ₃) δ 6.89 (d, J=8.8Hz, 1H), 6.85 (d, 2.8Hz, 1H), 6.49 (dd, J=8.8Hz, J=2.8Hz, 1H), 4.53 (q, J=14.6Hz, 2H), 3.93 (d, J=6.6Hz, 2H), 3.77 (s, 3H), 3.38 (t, J=6.8Hz, 2H), 3.29-3.22 (m, 1H), 2.80-2.77 (t, 6.4Hz, 1H), and 2.65-2.61 (t, J=6.0Hz, 1H), 2.29-2.00 (m, 5H), 1.88-1.84 (m, 2H), 1.65-1.53 (m, 4H), 0.94-0.87 (m, 6H); ¹³C NMR (CDCl ₃) δ 165.4,155.5,139.8,129.8,117.2,107.1,103.3,75.1,69.7,68.0,63.7,56.0,52.5,51.9,45.4,31.6,31.5,29.2,23.5,16.9,10.8; HPLC-MS (ammonium acetate) [M+H] ⁺=377.3.

Universal method 17 (GP17)

[0295] in the 7mL bottle, adds 4-(3-iodo-2-methyl-propyl)-6-methyl-4H-benzo [crude product of 1,4] oxazine-3-ketone (1 equivalent), Et ₃N (0.5mL) and secondary amine (1.2-1.5 equivalent).Mixture shakes 72h under 60 ℃, use MeOH (10mL) dilution subsequently, uses alkaline Al ₂O ₃(2g) concentrate, use purification by flash chromatography.

(R)-6-methyl-4-[2-methyl-3-(4-propoxyl group piperidyl-1)-propyl group]-4H-benzo [1,4] oxazine-3-ketone (101IS69)

[0296] according to GP17 make (S)-4-(3-iodo-2-methyl-propyl)-6-methyl-4H-benzo [crude product (0.23g) of 1,4] oxazine-3-ketone, 4-propoxyl group piperidines (and 0.12g, 81mmol) and Et ₃N (0.5mL) reaction.Quick CC (SiO ₂CH ₂Cl ₂/ acetone/MeOH 90: 5: 5) purification obtains title compound (0.20g, 83%). ¹H?NMR(CD ₃OD)δ6.97(brs，1H)，6.79(d，J＝8.0Hz，1H)，6.75(dm，J＝8.0Hz，1H)，4.47(brs，2H)，3.97(dd，J＝6.4，14.4Hz，1H)，8.82(dd，J＝7.2，14.4Hz，1H)，3.44(brs，1H)，3.33(t，J＝6.8Hz，2H)，3.10-2.90(m，2H)，2.90-2.6(m，3H)，2.29(m，1H)，2.24(s，3H)，1.98-1.86(m，2H)，1.78-1.64(m，2H)，1.47(tq，J＝14.4，7.2Hz，2H)，0.92(d，J＝6.4Hz)，0.83(t，J＝7.2Hz)； ¹³CNMR(CD ₃OD)δ166.4，143.8，132.8，128.3，124.7，116.7，116.1，69.9，67.4，61.5，50.7，50.5，44.1，28.9，28.6，23.0，20.0?15.6，9.8。

[0297] product is dissolved in ether, adds the oxalic acid (1.1 equivalent) that is dissolved in ether.Filter the crystal that forms, use washing with acetone, obtain the oxalates (0.204g) of title compound.HPLC-MS (ammonium acetate) [M+H] ⁺=361.3.

(R)-4-[3-(4-butylidene piperidyl-1) 2-methyl-propyl]-6-methyl-4H-benzo [1,4] oxazine-3-ketone (101IS71-A)

[0298] makes (S)-4-(3-iodo-2-methyl-propyl)-6-methyl-4H-benzo [crude product (0.34g) of 1,4] oxazine-3-ketone, Et according to GP17 ₃N (0.5mL) and 4-butylidene piperidines (0.17g, 1.2mmol) reaction.Quick CC (SiO ₂CH ₂Cl ₂/ acetone/MeOH 90: 7: 3) purification obtains title compound (0.22g, 58%). ¹H?NMR(CD ₃OD)δ7.01(s，1H)，6.86(d，J＝8.0Hz，1H)，6.82(dm，J＝8.0Hz，1H)，5.12(t，J＝7.2Hz，1H)，4.52(ABq，J＝14.8，20.8Hz，2H)，4.03(dd，J＝5.6，14.4Hz，1H)，3.91(dd，J＝8.0，14.4Hz，1H)，2.48-2.34(m，2H)，2.33-2.11(m，8H)，2.31(s，3H)，1.96(q，J＝7.2Hz，2H)，1.34(m，2H)，0.91-0.86(m，6H)； ¹³C?NMR(CD ₃OD)δ165.9，143.9，136.0，132.4，128.3，124.3，122.4，116.6，116.2，67.4，63.6，56.3，55.4，45.0，28.92，28.85，28.0，23.0，20.0，15.9，12.8。

[0299] product is dissolved in ether, adds the oxalic acid (1.1 equivalent) that is dissolved in ether.Filter the crystal that forms, use washing with acetone, obtain the oxalates (0.236g) of title compound.HPLC-MS (ammonium acetate) [M+H] ⁺=367.3.

(R)-4-[3-(4-butyl piperidine base-1)-2-methyl-propyl]-6-methyl-4H-benzo [1,4] oxazine-3-ketone (101IS71-D)

[0300] makes (S)-4-(3-iodo-2-methyl-propyl)-6-methyl-4H-benzo [crude product (0.30g) of 1,4] oxazine-3-ketone, Et according to GP17 ₃N (0.5mL) and 4-butyl piperidine (0.15g, 1.0mmol) reaction.Quick CC (SiO ₂CH ₂Cl ₂/ acetone/MeOH 90: 7: 3) purification obtains title compound (0.26g, 84%). ¹H?NMR(CD ₃OD)δ7.00(s，1H)，6.86(d，J＝8.0Hz，1H)，6.81(dm，J＝8.0Hz，1H)，4.52(ABq，J＝14.4，20.8Hz，2H)，3.99(dd，J＝6.0，14.4Hz，1H)，3.90(dd，J＝8.4，14.4Hz，1H)，2.97(brd，J＝11.2Hz，1H)，2.82(brd，J＝8.4Hz，1H)，2.39-2.10(m，2H)，2.31(s，3H)，2.07-1.88(m，2H)，1.73-1.62(m，2H)，1.35-1.18(m，9H)，0.94-0.08(m，6H)； ¹³C?NMR(CD ₃OD)δ166.0，143.8，132.4，128.3，124.3，116.6，116.2，67.4，63.6，55.0，54.2，44.8，36.2，35.6，32.1(br)，28.9，28.8，22.8，20.0，15.9，13.2。

[0301] product is dissolved in ether, adds the oxalic acid (1.1 equivalent) that is dissolved in ether.Filter the crystal that forms, use washing with acetone, obtain the oxalates (0.253g) of title compound.HPLC-MS (ammonium acetate) [M+H] ⁺=359.3.

(R)-4-[3-(3-butyl-8-azabicyclo [3.2.1] octyl group-8)-2-methyl-propyl]-6-methyl-4H-benzo [1,4] oxazine-3-ketone (101IS71-B3)

[0302] according to GP17 make (S)-4-(3-iodo-2-methyl-propyl)-6-methyl-4H-benzo [crude product of 1,4] oxazine-3-ketone (and 0.19g, 0.54mmol), Et ₃N (0.5mL) and 3-butyl-8-azabicyclo [3.2.1] octane (0.10g, 0.61mmol) reaction.Quick CC (SiO ₂CH ₂Cl ₂/ i-PrOH 92: 8) purification obtains title compound (0.13g, 62%). ¹H?NMR(CD ₃OD)δ7.05(s，1H)，6.86(d，J＝8.4Hz，1H)，6.81(dm，J＝8.4Hz，1H)，4.52(ABq?J＝14.8，24.8Hz，2H)，4.05(dd，J＝5.6，14.0Hz，1H)，3.94(dd，J＝8.8，14.0Hz，1H)，3.05-3.16(m，2H)，2.35-2.14(m，2H)，2.31(s，3H)，2.05-1.78(m，3H)，1.63-1.40(m，5H)，1.36-1.12(m，5H)，0.99(d，J＝6.4Hz，3H)，0.90(t，J＝6.8Hz，3H)； ¹³CNMR(CD ₃OD)δ167.4，144.9，133.7，129.2，125.6，117.7，117.3，68.5，63.2(br)，62.5(br)，56.0(br)，43.3，37.8(br)，31.3，30.5，30.0，28.3，26.7，26.4，23.7，21.0，16.8，14.2。

[0303] product is dissolved in ether, adds the oxalic acid (1.1 equivalent) that is dissolved in ether.Filter the crystal that forms, use washing with acetone, obtain the oxalates (0.104g) of title compound.HPLC-MS (ammonium acetate) [M+H] ⁺=349.3.

(R)-4-[3-(3-amyl group-8-azabicyclo [3.2.1] octyl group-8)-2-methyl-propyl]-6-methyl-4H-benzo [1,4] oxazine-3-ketone (101IS71-C3)

[0304] makes (S)-4-(3-iodo-2-methyl-propyl)-6-methyl-4H-benzo [crude product (0.15g) of 1,4] oxazine-3-ketone, Et according to GP17 ₃N (0.5mL) and 3-amyl group-8-azabicyclo [3.2.1] octane (95mg, 5.2mmol) reaction.Quick CC (SiO ₂CH ₂Cl ₂/ i-PrOH 92: 8) purification obtains title compound (0.12g, 68%). ¹H?NMR(CD ₃OD)δ7.06(s，1H)，6.86(d，J＝8.0Hz，1H)，6.81(brd，J＝8.0Hz，1H)，4.52(ABq，J＝14.8，27.2Hz，2H)，4.06(dd，J＝5.6，14.2Hz，1H)，4.96(dd，J＝8.8，14.2Hz，1H)，3.16-3.02(m，2H)，2.34-2.07(m，7H)，2.31(s，3H)，2.04-1.81(m，3H)，1.70-1.55(m，3H)，1.46-1.21(m，10H)，0.92-0.85(m，6H)； ¹³C?NMR(CD ₃OD)δ167.2，145.1，133.6，129.4，125.5，117.7，117.5，68.7，61.6，60.2，58.6，46.1，39.6，37.2，36.9，33.1，32.4，29.6，29.5，28.5，27.8，23.7，21.18，17.0，14.4。

[0305] product is dissolved in ether, adds the oxalic acid (1.1 equivalent) that is dissolved in ether.Filter the crystal that forms, use washing with acetone, obtain the oxalates (0.128g) of title compound.HPLC-MS (ammonium acetate) [M+H] ⁺=399.3.

1-[3-(propyl group of 4-propoxyl group piperidyl-1-)]-3,4-dihydro-1H-quinoline-2-one-(85LM32)

[0306] in the 4mL bottle, adds the 1-(3-chloro-propyl group)-3 that is dissolved among the MeCN (2mL), the crude product (0.200g) of 4-dihydro-1H-quinoline-2-one-(85LM31), 4-propoxyl group-piperidines (79KS-66) (0.130g, 0.897mmol), potassium carbonate (0.247g, 1.79mmol) and sodium iodide (0.269g, 1.79mmol), and under 50 ℃, shake 20h.Reactant mixture water (1mL) quencher, (3 * 1mL) extract product with EtOAc.Merge organic layer, use Na ₂SO ₄Drying, evaporation is with quick CC (SiO ₂MeOH/DCM 0: 1 → 3: 7) purification obtains title compound (85LM32) (0.012g, gross production rate 3%). ¹H NMR (CDCl ₃) δ 7.25 (t, J=7.4Hz, 1H), 7.18-7.08 (m, 2H), 6.98 (t, J=7.4Hz, 1H), 3.98 (t, J=7.6Hz, CH ₂), 3.38 (t, J=6.8Hz, CH ₂), 3.35-3.25 (m, 1H), 2.87 (t, J=7.6Hz, CH ₂), 2.80-2.70 (m, 2H), 2.65-2.60 (m, 2H), 2.45-2.35 (m, 2H), 2.20-2.10 (m, 2H), 1.95-1.80 (m, 4H), 1.65-1.50 (m, 4H), 0.95 (t, J=7.6Hz, CH ₃); ¹³C NMR (CDCl ₃) δ 170.2,140.0,128.2,127.5,126.6,122.8,115.3,70.0,56.0,51.8,40.5,32.0,31.5,25.8,25.2,22.8,10.7; HPLC-MS (ammonium acetate) [M+H] ⁺=331.3.

1-[3-(propyl group-6-fluoro-3 of 4-butyl piperidine base-1-), 4-dihydro-1H-quinoline-2-one-(92LH81)

[0307] in the 4mL bottle, add 1-(3-the chloropropyl)-6-fluoro-3 be dissolved among the MeCN, 4-dihydro-1H-quinoline-2-one-(92LH79) (0.090g, 0.37mmol), the 4-butyl piperidine (0.078g, 0.55mmol), KI (0.091g, 0.55mmol) and K ₂CO ₃(0.076g 0.55mmol), and shakes 20h under 50 ℃.The quencher of reactant mixture water, product extracts with EtOAc.Merge organic layer, use Na ₂SO ₄Drying is filtered, and concentrates.Product is with quick CC (SiO ₂EtOAc) purification obtains title compound (92LH81) (0.090g, 70%). ¹H NMR (CD ₃OD) δ 7.19-7.15 (m, 1H), 6.99-6.97 (m, 2H), 3.97 (t, J=6.4Hz, CH ₂), 2.90-2.87 (m, 4H), 2.59 (t, J=7.6Hz, CH ₂), 2.38 (t, J=7.6Hz, CH ₂); 1.96-1.78 (m, 4H), 1.67 (d, J=9.6Hz, 2H), 1.29-1.22 (m, 9H), 0.90-0.88 (m, 3H); ¹³C NMR (CD ₃OD) δ 172.1,160.0 (d, J=241.8Hz), 136.7 (d, J=2.3Hz), 130.6 (d, J=7.7Hz), 117.8 (d, J=8.1Hz), 115.9 (d, J=23.1Hz), 114.6 (d, J=22.7Hz), 57.0,55.0,41.6,37.4,36.9,33.1,32.4,30.1,26.2,25.5,23.9,14.4; HPLC-MS (ammonium acetate) [M+H] ⁺=347.33.

6-fluoro-1-[3-(propyl group of 4-propoxyl group piperidyl-1-)]-3,4-dihydro-1H-quinoline-2-one-(107LH70)

[0308] in the 4mL bottle, adds 1-(3-the chloropropyl)-6-fluoro-3 that is dissolved among the MeCN (2mL), 4-dihydro-1H-quinoline-2-one-(92LH79) (0.242g, 1.00mmol), 4-propoxyl group piperidines (0.143g, 1.00mmol), KI (0.250g, 1.50mmol) and K ₂CO ₃(0.207g 1.50mmol), and shakes 20h under 40 ℃.The quencher of reactant mixture water, product extracts with EtOAc.Merge organic layer, use Na ₂SO ₄Drying is filtered, and concentrates.Product is with quick CC (SiO ₂EtOAc, MeOH/EtOAc 1: 4) purification, obtain title compound (107LH70) (0.165g, 47%). ¹HNMR (CD ₃OD) δ 7.19-7.15 (m, 1H), 7.01-6.97 (m, 2H), 3.96 (t, J=7.4Hz, CH ₂), 3.40 (t, J=6.6Hz, CH ₂), 3.35-3.30 (m, 3H), 2.88 (t, J=6.8Hz, 2H), 2.76 (m, 2H), 2.60-2.57 (m, 2H), 2.43-2.39 (m, 2H), 2.22-2.1 7 (m, 2H), 1.90-1.78 (m, 4H), 1.61-1.50 (m, 4H), 0.91 (t, J=7.4Hz, CH ₃); ¹³C NMR (CD ₃OD) δ 172.2,160.0 (d, J=242.2Hz), 136.7 (d, J=2.3Hz), 130.6 (d, J=7.7Hz), 117.8 (d, J=8.5Hz), 115.9 (d, J=23.1Hz), 114.64 (d, J=22.3Hz), 75.6,70.7,56.5,52.0,41.6,32.4,31.8,26.1,25.5,24.2,11.0; HPLC-MS (ammonium acetate) [M+H] ⁺=349.30.

(R, S)-1-[3-(4-butyl piperidine base-1)-2-methyl-propyl]-6-fluoro-3,4-dihydro-1H-quinoline-2-one- (107LH71-1)

[0309] in the 4mL bottle, adds (the R that is dissolved among the DMF (2mL), S)-1-(3-chloro-2-methyl-propyl)-6-fluoro-3, the crude product (0.154g) of 4-dihydro-1H-quinoline-2-one-(107LH68), 4-butyl piperidine (0.141g, 1.0mmol), KI (0.250g, 1.5mmol) and K ₂CO ₃(0.207g 1.5mmol), and shakes 20h under 100 ℃.The quencher of reactant mixture water, product extracts with EtOAc.Merge organic layer, use Na ₂SO ₄Drying is filtered, and concentrates.Crude product cation exchange CC and quick CC (SiO ₂EtOAc) purification obtains title compound (107LH77-1) (0.069g, gross production rate 13%). ¹HNMR(CD ₃OD)δ7.22-7.18(m，1H)，7.00-6.93(m，1H)，3.94(d，J＝6.8Hz，2H)，2.91-2.86(m，3H)，2.74(d，J＝10.2Hz，1H)，2.62-2.158(m，2H)，2.24-2.02(m，3)，1.90-1.81(m，2H)，1.66-1.61(m，2H)，1.30-1.19(m，9H)，0.89(t，J＝6.6Hz，CH ₃)，0.86(d，J＝6.7Hz，CH ₃)； ¹³C?NMR(CD ₃OD)δ172.7，160.0(d，J＝241.8Hz)，136.7(d，J＝2.7Hz)，130.9(d，J＝8.1Hz)，118.4(d，J＝8.1Hz)，115.9(d，J＝23.5Hz)，114.4(d，J＝22.7Hz)，65.0，56.1，55.6，46.9，37.5，37.0，33.5，33.4，32.6，30.1，30.1，26.2，24.0，17.2，14.4。

[0310] product is dissolved in acetone, adds the oxalic acid that is dissolved in acetone.Filter the crystal that forms, use washing with acetone, obtain the oxalates (0.076g) of title compound.HPLC-MS (ammonium acetate) [M+H] ⁺=361.32.

(R, S)-6-fluoro-1-[3-(4-propoxyl group piperidyl-1)-2-methyl-propyl]-3,4-dihydro-1H-quinoline-2-one- (107LH71-2)

[0311] in the 4mL bottle, adds (the R that is dissolved among the DMF (2mL), S)-1-(3-chloro-2-methyl-propyl)-6-fluoro-3, the crude product (0.154g) of 4-dihydro-1H-quinoline-2-one-(107LH68), 4-propoxyl group piperidines (0.143g, 1.0mmol), KI (0.250g, 1.5mmol) and K ₂CO ₃(0.207g 1.5mmol), and shakes 20h under 100 ℃.The quencher of reactant mixture water, product extracts with EtOAc.Merge organic layer, use Na ₂SO ₄Drying is filtered, and concentrates.Crude product cation exchange CC and quick CC (SiO ₂EtOAc) purification obtains title compound (107LH77-2) (0.053g, gross production rate 10%). ¹H?NMR(CD ₃OD)δ7.23-7.19(m，1H)，7.00-6.95(m，1H)，3.95(d，J＝7.0Hz，2H)，3.41(t，J＝6.6Hz，CH ₂)，3.31-3.27(m，1H)，2.90(t，J＝6.6Hz，2H)，2.74-2.71(m，1H)，2.64-2.58(m，3H)，2.26-2.00(m，5H)，1.89-1.85(m，2H)，1.60-1.49(m，4H)，0.91(t，J＝7.4Hz，CH ₃)，0.86(d，J＝6.7Hz，CH ₃)； ¹³CNMR(CD ₃OD)δ172.7，160.0(d，J＝242.2Hz)，136.7(d，J＝2.7Hz)，130.9(d，J＝7.7Hz)，118.3(d，J＝8.1Hz)，115.9(d，J＝23.1Hz)，114.5(d，J＝22.7Hz)，76.4，70.7，64.4，53.2，52.8，46.9，32.5，32.4，32.3，30.3，26.17，26.15，24.2，17.1，11.0。

[0312] product is dissolved in acetone, adds the oxalic acid that is dissolved in acetone.Filter the crystal that forms, use washing with acetone, obtain the oxalates (0.048g) of title compound.HPLC-MS (ammonium acetate) [M+H] ⁺=363.30.

1-[3-(propyl group of 4-butyl piperidine base-1-)]-6-chloro-3,4-dihydro-1H-quinoline-2-one-(107LH36)

[0313] in argon, in reaction flask, add the 6-chloro-3 that is dissolved in dried DMF (2mL), and 4-dihydro-1H-quinoline-2-one-(107LH30) (0.100g, 0.55mmol).Adding NaH (contain 60% in the oil, 0.024g, 0.60mmol), mixture at room temperature stirs 0.5h.(0.087g 0.55mmol), stirs 20h at 30 ℃ then to add 1-bromo-3-chloropropane then.The quencher of reactant mixture water, product extracts with EtOAc.Merge organic layer, use Na ₂SO ₄Drying is filtered, and concentrates.Crude product is dissolved among the MeCN (3mL), add then the 4-butyl piperidine (0.078g, 0.055mmol), KI (0.166g, 1.00mmol) and K ₂CO ₃(0.138g 1.00mmol), and shook 2 days at 50 ℃.The quencher of reactant mixture water, product extracts with EtOAc.Merge organic layer, use Na ₂SO ₄Drying is filtered, and concentrates.Product preparation property RP-HPLC purification obtains title compound (107LH36) (0.047g, 24%). ¹H NMR (CD ₃OD) δ 7.25-7.13 (m, 3H), 3.96 (t, J=7.2Hz, CH ₂), 2.95-2.86 (m, 4H), 2.61-2.57 (m, 2H), 2.45-2.41 (m, 2H), 2.04-1.98 (m, 2H), 1.87-1.79 (m, 2H), 1.28-1.18 (m, 9H), 0.90 (t, J=7.0Hz, CH ₃); ¹³CNMR (CD ₃OD) δ 172.3,139.2, and 130.2,129.3,128.9,128.4,117.8,56.8,54.9,41.4,37.2,36.6,32.9,32.4,30.0,26.0,25.3,23.9,14.4; HPLC-MS (ammonium acetate) [M+H] ⁺=363.28.

1-[3-(propyl group of 4-butyl piperidine base-1-)]-6-methyl-3,4-dihydro-1H-quinoline-2-one-(107LH18-1)

[0314] in the 4mL bottle, adds 1-(3-the chloropropyl)-6-methyl-3 that is dissolved among the MeCN (2mL), the crude product (0.128g) of 4-dihydro-1H-quinoline-2-one-(107LH14), 4-butyl piperidine (0.076g, 0.54mmol), KI (0.166g, 1.00mmol) and K ₂CO ₃(0.138g 1.00mmol), and shakes 20h under 50 ℃.The quencher of reactant mixture water, product extracts with EtOAc.Merge organic layer, use Na ₂SO ₄Drying is filtered, and concentrates.Product is with quick CC (SiO ₂EtOAc, MeOH/EtOAc1: 4) purification obtains title compound (107LH18-1) (0.088g, gross production rate 41%). ¹HNMR (CD ₃OD) δ 7.07-7.01 (m, 3H), 3.94 (t, J=7.4Hz, CH ₂), 2.90-2.80 (m, 4H), 2.57-2.53 (m, 2H), 2.39-2.33 (m, 2H), 2.27 (s, 3H, CH ₃), 1.95-1.90 (m, 2H), 1.85-1.79 (m, 2H), 1.66 (d, J=9.8Hz, 2H), 1.30-1.17 (m, 9H), 0.89 (t, J=6.8Hz, CH3); ¹³C NMR (CD ₃OD) δ 172.4,137.9, and 134.1,129.8,129.0,128.0,116.3,57.1,55.0,41.3,37.4,36.8,33.1,32.8,30.1,26.2,25.5,23.9,20.7,14.4; HPLC-MS (ammonium acetate) [M+H] ⁺=343.33.

6-methyl isophthalic acid-[3-(propyl group-3 of 4-propoxyl group piperidyl-1-), 4-dihydro-1H-quinoline-2-one-(107LH18-2)

[0315] in the 4mL bottle, add 1-(3-the chloropropyl)-6-methyl-3 be dissolved among the MeCN (2mL), 4-dihydro-1H-quinoline-2-one-(107LH14) (0.128g), 4-propoxyl group piperidines (0.079g, 0.54mmol), KI (0.166g, 1.0mmol) and K ₂CO ₃(0.138g 1.0mmol), and shakes 20h under 50 ℃.The quencher of reactant mixture water, product extracts with EtOAc.Merge organic layer, use Na ₂SO ₄Drying is filtered, and concentrates.Product is with quick CC (SiO ₂EtOAc, MeOH/EtOAc1: 4) purification obtains title compound (107LH18-2) (0.108g, gross production rate 50%). ¹HNMR (CD ₃OD) δ 7.05-7.00 (m, 3H), 3.95 (t, J=7.2, CH ₂), 3.41-3.30 (m, 3H), 2.84-2.76 (m, 4H), 2.57-2.53 (m, 2H), 2.47-2.43 (m, 2H), 2.27 (s, 3H, CH ₃), 2.27-2.22 (m, 2H), 1.90-1.81 (m, 4H), 1.63-1.52 (m, 4H), 0.91 (t, J=7.4Hz, CH ₃); ¹³C NMR (CD ₃OD) δ 172.4,137.8, and 134.0,129.8,129.0,128.0,116.2,75.3,70.7,56.5,51.9,41.2,32.8,31.7,26.2,25.5,24.3,20.7,11.0; HPLC-MS (ammonium acetate) [M+H] ⁺=345.30.

1-[3-(propyl group of 4-butyl piperidine base-1-)]-7-fluoro-3,4-dihydro-1H-quinoline-2-one-(107LH21)

[0316] in argon, in reaction flask, add the 7-fluoro-3 that is dissolved in dried DMF (2mL), and 4-dihydro-1H-quinoline-2-one-(97LH36) (0.080g, 0.48mmol).Adding NaH (contain 60% in the oil, 0.021g, 0.53mmol), mixture at room temperature stirs 0.5h.(0.075g 0.48mmol), at room temperature stirs 20h then to add 1-bromo-3-chloropropane then.The quencher of reactant mixture water, product extracts with EtOAc.Merge organic layer, use Na ₂SO ₄Drying is filtered, and concentrates.Crude product is dissolved among the MeCN (3mL), add then the 4-butyl piperidine (0.071g, 0.50mmol), KI (0.166g, 1.00mmol) and K ₂CO ₃(0.138g 1.00mmol), and shook 4 days at 50 ℃.The quencher of reactant mixture water, product extracts with EtOAc.Merge organic layer, use Na ₂SO ₄Drying is filtered, and concentrates.Product is with quick CC (SiO ₂EtOAc) purification obtains title compound (107LH21) (0.062g, 37%). ¹HNMR (CD ₃OD) δ 7.20-7.17 (m, 1H), 7.01-6.98 (m, 1H), 6.76-6.72 (m, 1H), 3.95 (t, J=7.4Hz, CH ₂), 2.93-2.84 (m, 4H), 2.61-2.57 (m, 2H), 2.42-2.38 (m, 2H), 2.00-1.94 (m, 2H), 1.84-1.80 (m, 2H), 1.68 (d, J=10.0Hz, 2H), 1.30-1.22 (m, 9H), 0.89 (t, J=6.8Hz, CH ₃); HPLC-MS (ammonium acetate) [M+H] ⁺=347.31.

1-[3-(propyl group of 4-butyl piperidine base-1-)]-5-methyl-3,4-dihydro-1H-quinoline-2-one-(107LH28)

[0317] in the 4mL bottle, adds 1-(3-the chloropropyl)-5-methyl-3 that is dissolved among the MeCN, 4-dihydro-1H-quinoline-2-one-(107LH27-11,3) (0.057g, 0.24mmol), 4-butyl piperidine (0.042g, 0.30mmol), KI (0.083g, 0.50mmol) and K ₂CO ₃(0.069g 0.50mmol), and shakes under 50 ℃.The quencher of reactant mixture water, product extracts with EtOAc.Merge organic layer, use Na ₂SO ₄Drying is filtered, and concentrates.Product is with quick CC (SiO ₂EtOAc, MeOH/EtOAc 1: 4) purification, obtain title compound (107LH28) (0.060g, 74%). ¹H NMR (CD ₃OD) δ 7.15 (t, J=8.0Hz, 1H), 7.03 (d, J=8.2Hz, 1H), 6.92 (d, J=7.4Hz), 4.00 (t, J=7.2Hz, CH ₂), 3.10 (d, J=12.1Hz, 2H), 2.87-2.83 (m, 2H), 2.66-2.62 (m, 2H) 2.59-2.55 (m, 2H), 2.31-2.25 (m, 2H), 2.29 (s, CH ₃), 1.93-1.87 (m, 2H), 1.76 (d, J=11.7Hz, 2H), 1.31-1.24 (m, 9H), 0.90 (t, J=6.8Hz, CH ₃); ¹³C NMR (CD ₃OD) δ 172.7,140.2, and 137.0,128.1,126.6,126.5,114.5,56.5,54.6,41.2,37.0,36.0,32.2,32.2,30.0,25.0,23.9,22.4,19.7,14.4; HPLC-MS (ammonium acetate) [M+H] ⁺=343.36.

1-[3-(propyl group of 4-butyl piperidine base-1-)] 7-methyl-3 4-dihydro-1H-quinoline-2-one-(107LH29)

[0318] in the 4mL bottle, adds 1-(3-the chloropropyl)-7-methyl-3 that is dissolved among the MeCN, 4-dihydro-1H-quinoline-2-one-(107LH27-13,1) (0.117g, 0.49mmol), 4-butyl piperidine (0.071g, 0.50mmol), KI (0.166g, 1.00mmol) and K ₂CO ₃(0.138g 1.00mmol), and shakes under 50 ℃.The quencher of reactant mixture water, product extracts with EtOAc.Merge organic layer, use Na ₂SO ₄Drying is filtered, and concentrates.Product is with quick CC (SiO ₂EtOAc, MeOH/EtOAc 1: 4) purification, obtain title compound (107LH28) (0.060g, 74%). ¹H NMR δ 7.06 (d, J=7.4Hz, 1H), 6.97 (s, 1H), 6.84 (d.J=7.6Hz, 1H), 3.97 (t, J=7.4Hz, CH ₂), 2.91 (d, J=11.2Hz, 2H), 2.82 (t, J=6.8Hz, CH ₂), 2.57-2.54 (m, 2H), 2.41-2.37 (m, 2H), 2.33 (s, CH ₃), 1.98-1.92 (m, 2H), 1.87-1.79 (m, 2H), 1.68 (d, J=9.6Hz, 2H), 1.30-1.17 (m, 9H), 0.89 (t, J=6.8Hz, CH ₃); ¹³C NMR (CD ₃OD) δ 172.7,140.1, and 138.5,128.9,125.1,124.9,117.0,57.0,55.0,41.3,37.3,36.8,33.1,30.1,25.8,25.6,23.9,21.6,14.4; HPLC-MS (ammonium acetate) [M+H] ⁺=343.37.

1-[3-(propyl group of 4-butyl piperidine base-1-)]-7-fluoro-6-methyl-3,4-dihydro-1H-quinoline-2-one- (112KK06)

[0319] in the 4mL bottle, adds 1-(3-the chloropropyl)-7-fluoro-6-methyl-3 that is dissolved among the MeCN (2mL), 4-dihydro-1H-quinoline-2-one-(112KK01) (0.047g, 0.18mmol), the 4-butyl piperidine (0.039g, 0.28mmol), NaI (0.100g, 0.67mmol) and K ₂CO ₃(0.075g 0.54mmol), and shakes 20h under 50 ℃.The quencher of reactant mixture water, product extracts with EtOAc.Merge organic layer,, use quick CC (SiO then with cation exchange CC purification ₂MeOH/DCM 1: 10) purification obtains title compound (112KK06) (0.022g, 34%). ¹H?NMR(CD ₃OD)δ7.05(d，J＝8.4Hz，1H)，6.93(d，J＝11.7Hz，1H)，3.93(t，J＝7.2Hz，CH ₂)，2.93(d，J＝11.1Hz，2H)，2.83(t，J＝6.9Hz，CH ₂)，2.60-2.56(m，2H)，2.44-2.40(m，2H)，2.19(d，J＝1.8Hz，CH ₃)2.03-1.98(m，2H)，1.86-1.79(m，2H)，1.69(d，J＝11.0Hz，2H)，1.31-1.19(m，9H)，0.89(t，J＝6.6Hz，CH ₃)； ¹³C?NMR(CD ₃OD)δ172.4，161.7(d，J＝241.0Hz)，139.5(d，J＝10.0Hz)，131.7(d，J＝6.1Hz)，123.5(d，J＝3.6Hz)，119.9(d，J＝17.4Hz)，104.0(d，J＝28.1Hz)，56.8，55.0，41.5，37.3，36.7，33.0，32.8，30.1，25.5，25.3，23.9，14.4，13.7。

[0320] product is dissolved in MeOH/Et ₂Among the O, adding is dissolved in Et ₂Oxalic acid among the O.Filter the crystal that forms, use washing with acetone, obtain the oxalates (0.018g) of title compound.HPLC-MS (ammonium acetate) [M+H] ⁺=361.35.

1-[3-(propyl group of 4-butyl piperidine base-1-)]-6,7-two fluoro-3,4-dihydro-1H-quinoline-2-one-(112KK07)

[0321] in the 4mL bottle, adds the 1-(3-chloropropyl)-6 that is dissolved among the MeCN (2mL), 7-two fluoro-3, and 4-dihydro-1H-quinoline-2-one-(112KK03) (0.123g, 0.47mmol), 4-butyl piperidine (0.074g, 0.52mmol), NaI (0.100g, 0.67mmol) and K ₂CO ₃(0.075g 0.54mmol), and shakes 20h under 50 ℃.The quencher of reactant mixture water, product extracts with EtOAc.Merge organic layer,, use quick CC (SiO then with cation exchange CC purification ₂MeOH/DCM 1: 10) purification obtains title compound (112KK07) (0.097g, 57%). ¹H?NMR(CD ₃OD)δ7.20-7.09(m，2H)，3.91(t，J＝7.2Hz，CH ₂)，2.90-2.82(m，4H)，2.59-2.55(m，2H)，2.38-2.34(m，2H)，1.97-1.91(m，2H)，1.82-1.75(m，2H)，1.66(d，J＝9.8Hz，2H)，1.28-1.16(m，9H)，0.87(t，J＝6.7Hz，CH ₃)； ¹³C?NMR(CD ₃OD)δ172.1，150.4(q，J＝243.2Hz，J＝13.2Hz)，146.9(q，J＝243.2Hz，J＝12.6Hz)，137.3(q，J＝8.1Hz，J＝2.9Hz)，124.9(q，J＝5.8Hz，J＝3.9Hz)，117.6(d，J＝18.7Hz)，106.4(d，J＝22.6Hz)，56.8，55.0，41.8，37.4，36.8，33.1，32.4，30.1，25.5，25.3，23.9，14.4。

[0322] product is dissolved in MeOH/Et ₂Among the O, adding is dissolved in Et ₂Oxalic acid among the O.Filter the crystal that forms, use washing with acetone, obtain the oxalates (0.046g) of title compound.HPLC-MS (ammonium acetate) [M+H] ⁺=365.32.

6, and 7-two fluoro-1-[3-(propyl group of 4-propoxyl group piperidyl-1-)]-3,4-dihydro-1H-quinoline-2-one-(122LH7)

[0323] in the 4mL bottle, adds the 1-(3-chloropropyl)-6 that is dissolved among the MeCN (2.5mL), 7-two fluoro-3, and 4-dihydro-1H-quinoline-2-one-(112KK03) (0.286g, 1.1mmol), 4-propoxyl group piperidines (0.160g, 1.1mmol), KI (0.250g, 1.5mmol) and K ₂CO ₃(0.207g 1.54mmol), and shook under 40 ℃ 2 days.The quencher of reactant mixture water, product extracts with EtOAc.Merge organic layer, use Na ₂SO ₄Drying is filtered, and concentrates.Crude product cation exchange CC, quick CC (SiO ₂EtOAc) and preparation property RP-HPLC purification, obtain title compound (122LH07) (0.165g, 41%). ¹H?NMR(CD ₃OD)δ7.22-7.11(m，2H)，3.94(t，J＝7.2Hz，CH ₂)，3.42-3.35(m，3H)，2.89-2.83(m，4H)，2.62-2.5?1(m，4H)，2.40-2.36(m，2H)，1.95-1.82(m，4H)，1.69-1.51(m，4H)，0.91(t，J＝7.2Hz，CH ₃)； ¹³CNMR(CD ₃OD)δ172.0，150.3(q，J＝243.3Hz，J＝13.5Hz)，146.9(q，J＝243.3Hz，J＝12.7Hz)，137.3(q，J＝8.1Hz，J＝2.7Hz)，124.9(q，J＝5.8Hz，J＝3.8Hz)，117.6(d，J＝18.8Hz)，106.3(d，J＝22.7Hz)，74.8，70.7，56.1，51.7，41.5，32.3，31.4，25.5，25.1，24.3，11.0。

[0324] product is dissolved in acetone, adds the oxalic acid that is dissolved in acetone.Filter the crystal that forms, use washing with acetone, obtain the oxalates (0.154g) of title compound.HPLC-MS (ammonium acetate) [M+H] ⁺=367.25.

(R, S)-1-[3-(4-butyl piperidine base-1)-2-methyl-propyl]-6,7-two fluoro-3,4-dihydro-1H-quinoline-2-one- (122LH11-1)

[0325] in argon, in reaction flask, add to be dissolved in and do 6 among the DMF (1mL), 7-two fluoro-3,4-dihydro-1H-quinoline-2-one-(97KK47) (0.183g, 1.0mmol).Adding NaH (contain 60% in the oil, 0.050g, 1.3mmol), mixture at room temperature stirs 0.5h.Add then (R, S)-(0.172g 1.0mmol), at room temperature stirs 20h to 1-bromo-3-chloro-2-methylpropane then.The quencher of reactant mixture water, product extracts with EtOAc.Merge organic layer, use Na ₂SO ₄Drying is filtered, and concentrates.With quick CC (SiO ₂EtOAc/ normal heptane 1: 1) behind the purification, crude product is dissolved among the DMF (0.5mL), add the 4-butyl piperidine (0.085g, 0.6mmol), NaI (0.113g, 0.075mmol) and K ₂CO ₃(0.104g 0.075mmol), stirred 3 days down at 50 ℃ then.The quencher of reactant mixture water, product extracts with EtOAc.Merge organic layer, use Na ₂SO ₄Drying is filtered, and concentrates.Crude product obtains title compound (122LH11-1) with cation exchange CC and preparation property RP-HPLC purification. ¹H?NMR(CD ₃OD)δ7.25-7.20(m，1H)，7.16-7.12(m，1H)，3.97(dd，J＝14.3Hz，J＝8.4Hz，1H)，3.85(dd，J＝14.5Hz，J＝5.1Hz，1H)，2.94-2.85(m，3H)，2.78(d，J＝9.4Hz，1H)，2.66-2.57(m，2H)，2.27-2.13(m，2H)，2.03-1.85(m，3H)，1.67-1.65(m，2H)，1.31-1.22(m，9H)，0.90(t，J＝6.6Hz，CH ₃)，0.87(d，J＝6.7Hz，CH ₃)。

[0326] product is dissolved in acetone, adds the oxalic acid that is dissolved in acetone.Filter the crystal that forms, use washing with acetone, obtain the oxalates (0.025g, 7%) of title compound.HPLC-MS (ammonium acetate) [M+H] ⁺=379.27.

(R, S)-6,7-two fluoro-1-[3-(4-propoxyl group piperidyl-1)-2-methyl-propyl]-3,4-dihydro-1H-quinoline-2- Ketone (122LH11-2)

[0327] in argon, in reaction flask, add to be dissolved in and do 6 among the DMF (1mL), 7-two fluoro-3,4-dihydro-1H-quinoline-2-one-(97KK47) (0.183g, 1.0mmol).Adding NaH (contain 60% in the oil, 0.050g, 1.3mmol), mixture at room temperature stirs 0.5h.Add then (R, S)-(0.172g 1.0mmol), at room temperature stirs 20h to 1-bromo-3-chloro-2-methylpropane then.The quencher of reactant mixture water, product extracts with EtOAc.Merge organic layer, use Na ₂SO ₄Drying is filtered, and concentrates.With quick CC (SiO ₂EtOAc/ normal heptane 1: 1) behind the purification, crude product is dissolved among the DMF (0.5mL), add the 4-butyl piperidine (0.085g, 0.6mmol), NaI (0.113g, 0.075mmol) and K ₂CO ₃(0.104g 0.075mmol), stirred 3 days down at 50 ℃ then.The quencher of reactant mixture water, product extracts with EtOAc.Merge organic layer, use Na ₂SO ₄Drying is filtered, and concentrates.Crude product obtains crude product title compound (122LH11-2) with cation exchange CC and preparation property RP-HPLC purification. ¹H?NMR(CD ₃OD)δ7.24-7.12(m，2H)，3.97(dd，J＝14.5Hz，J＝8.6Hz，1H)，3.87(dd，J＝14.3Hz，J＝5.1Hz，1H)，3.41(t，J＝6.7Hz，CH ₂)，3.35-3.28(m，1H)，2.89-2.85(m，2H)，2.78-2.75(m，1H)，2.66-2.59(m，3H)，2.26-2.21(m，1H)，2.17-2.11(m，2H)，2.07-1.97(m，2H)，1.90-1.86(m，2H)，1.61-1.51(m，4H)，0.92(t，J＝7.4Hz，CH ₃)，?0.86(d，J＝6.6Hz，CH ₃)； ¹³CNMR(CD ₃OD)δ172.5，150.3(q，J＝242.9Hz，J＝13.1Hz)，146.8(q，J＝243.3Hz，J＝13.1Hz)，137.3(q，J＝8.1Hz，J＝2.7Hz)，125.1(q，J＝5.8Hz，J＝3.8Hz)，117.6(d，J＝18.8Hz)，106.7(d，J＝22.7Hz)，76.3，70.9，64.5，53.4，52.8，47.1，32.5，32.4，30.5，25.5，24.3，17.2，11.0。

[0328] product is dissolved in acetone, adds the oxalic acid that is dissolved in acetone.Filter the crystal that forms, use washing with acetone, obtain the oxalates (0.030g, 8%) of title compound.HPLC-MS (ammonium acetate) [M+H] ⁺=381.27.

1-[3-(propyl group of 4-butyl piperidine base-1-)]-6-fluoro-7-methyl-3,4-dihydro-1H-quinoline-2-one- (107LH93-1)

[0329] at N ₂Add the 6-fluoro-7-methyl-3 that is dissolved among the dried DMF (1mL) in the downhill reaction flask, and 4-dihydro-1H-quinoline-2-one-(0.150g, 0.84mmol).(contain 60% in the oil, 0.038g 0.92mmol), and at room temperature stirs 30min to add NaH.(0.131g 0.84mmol), at room temperature stirs 20h then to add 3-chloro-propyl iodide then.The quencher of reactant mixture water, product extracts with EtOAc.Merge organic layer, use Na ₂SO ₄Drying is filtered, and concentrates.Crude product is dissolved among the MeCN (2mL), add then the 4-butyl piperidine (0.085g, 0.6mmol), NaI (0.150g, 1.0mmol) and K ₂CO ₃(0.138g 1.0mmol), and shakes 20h under 50 ℃.The quencher of reactant mixture water, product extracts with EtOAc.Merge organic layer, use Na ₂SO ₄Drying is filtered, and concentrates.Residue is used quick CC (SiO then with cation exchange CC purification ₂EtOAc) purification obtains title compound (107LH93-1) (0.166g, gross production rate 55%). ¹H?NMR(CH ₃OD)δ7.00(d，J＝6.4Hz，1H)，6.88(d，J＝9.2Hz，1H)，3.98-3.91(m，2H)，2.93-2.86(m，2H)，2.85-2.78(m，2H)，2.58-2.52(m，2H)，2.40-2.43(m，2H)，2.25(d，J＝2.0Hz，3H)，1.98-1.76(m，4H)，1.70-1.62(m，2H)，1.35-1.22(m，9H)，0.88(t，J＝7.0Hz，3H)； ¹³CNMR(CH ₃OD)δ171.1，157.2(d，J＝241Hz)，135.1(d，J＝3Hz)，126.5(d，J＝8Hz)，123.2(d，J＝18Hz)，118.1(d，J＝5Hz)，114.3(d，J＝24Hz)，55.8，43.9，40.4，36.2，35.7，32.0，31.5，29.0，24.6，24.3，22.8，13.4(br)。

[0330] product is dissolved in acetone, adds the oxalic acid (1.1 equivalent) that is dissolved in acetone.Filter the crystal that forms, use washing with acetone, obtain the oxalates (0.172g) of title compound.HPLC-MS (ammonium acetate) [M+H] ⁺=363.4.

6-fluoro-7-methyl isophthalic acid-[3-(propyl group of 4-propoxyl group piperidyl-1-)]-3,4-dihydro-1H-quinoline-2-one- (107LH93-2)

[0331] at N ₂Add the 6-fluoro-7-methyl-3 that is dissolved among the dried DMF (1mL) in the downhill reaction flask, and 4-dihydro-1H-quinoline-2-one-(0.150g, 0.84mmol).(contain 60% in the oil, 0.038g 0.92mmol), and at room temperature stirs 30min to add NaH.(0.131g 0.84mmol), at room temperature stirs 20h then to add 3-chloro-propyl iodide then.The quencher of reactant mixture water, product extracts with EtOAc.Merge organic layer, use Na ₂SO ₄Drying is filtered, and concentrates.Crude product is dissolved among the MeCN (2mL), add then 4-propoxyl group piperidines (0.086g, 0.6mmol), NaI (0.150g, 1.0mmol) and K ₂CO ₃(0.138g 1.0mmol), and shakes 20h under 50 ℃.The quencher of reactant mixture water, product extracts with EtOAc.Merge organic layer, use Na ₂SO ₄Drying is filtered, and concentrates.Residue is used quick CC (SiO then with cation exchange CC purification ₂EtOAc) purification obtains title compound (107LH93-2) (0.171g, gross production rate 56%). ¹H?NMR(CH ₃OD)δ7.00(d，J＝6.4Hz，1H)，6.87(d，J＝9.2Hz，1H)，3.94(brt，J＝7.2Hz，2H)，3.39(t，J＝6.6Hz，2H)，3.35-3.26(m，1H)，2.85-2.70(m，4H)，2.58-2.51(m，2H)，2.39(brt，7.4Hz，2H)，2.24(d，J＝1.6Hz，3H)，2.21-2.12(m，2H)，1.92-1.75(m，4H)，1.62-1.48(m，4H)，0.91(t，J＝7.4Hz)； ¹³C?NMR(CH ₃OD)δ171.0，157.1(d，J＝241)，135.2(d，J＝3Hz)，126.5(d，J＝8Hz)，123.2(d，J＝18Hz)，118.1(d，J＝5Hz)，114.3(d，J＝24Hz)，74.6，69.5，55.4，51.0，40.4，31.5，30.9，24.7，24.5，23.2，13.5(br)，10.0。

[0332] product is dissolved in acetone, adds the oxalic acid (1.1 equivalent) that is dissolved in acetone.Filter the crystal that forms, use washing with acetone, obtain the oxalates (0.172g) of title compound.HPLC-MS (ammonium acetate) [M+H] ⁺=364.3.

(R, S)-1-[3-(4-butyl piperidine base-1)-2-methyl-propyl]-6-fluoro-7-methyl-3,4-dihydro-1H-quinoline -2-ketone (107LH94-1)

[0333] at N ₂Add the 6-fluoro-7-methyl-3 that is dissolved among the dried DMF (1mL) in the downhill reaction flask, and 4-dihydro-1H-quinoline-2-one-(0.150g, 0.84mmol).(contain 60% in the oil, 0.038g 0.92mmol), and at room temperature stirs 30min to add NaH.Add then (R, S)-(0.144g 0.84mmol), at room temperature stirs 20h to 1-bromo-3-chloro-2-methylpropane then.The quencher of reactant mixture water, product extracts with EtOAc.Merge organic layer, use Na ₂SO ₄Drying is filtered, and concentrates.Crude product is dissolved in to be done among the DMF (2mL), add then the 4-butyl piperidine (0.085g, 0.6mmol), NaI (0.150g, 1.0mmol) and K ₂CO ₃(0.138g 1.0mmol), and shakes 20h under 100 ℃.The quencher of reactant mixture water, product extracts with EtOAc.Merge organic layer, use Na ₂SO ₄Drying is filtered, and concentrates.Residue is used quick CC (SiO then with cation exchange CC purification ₂EtOAc) purification obtains title compound (107LH94-1) (0.045g, gross production rate 14%). ¹H?NMR(CH ₃OD)δ7.01(d，J＝6.4Hz，1H)，6.90(d，J＝9.2Hz)，4.03-3.88(m，2H)，2.90(brd，J＝10.8Hz，2H)，2.83(brt，J＝7.0Hz，2H)，2.75(brd，J＝10.2Hz)，2.64-2.50(m，2H)，2.26-1.98(m，6H)，1.93-1.78(m，2H)，1.68-1.58(m，2H)，1.35-1.148(m，9H)，0.89(t，J＝6.8Hz，3H)，0.84(d，J＝6.8Hz，3H)； ¹³C?NMR(CH ₃OD)δ171.6，156.1(d，J＝241Hz)，135.1(d，J＝3Hz)，126.9(d，J＝8Hz)，123.0，(d，J＝19Hz)，118.6(d，J＝5Hz)，114.3(d，J＝24Hz)，63.9，55.1，54.4，45.5，36.3，35.9，32.4(br)，31.6，29.0，28.8，24.6，22.8，16.0，13.5(br)。

[0334] product is dissolved in acetone, adds the oxalic acid (1.1 equivalent) that is dissolved in acetone.Filter the crystal that forms, use washing with acetone, obtain the oxalates (0.037g) of title compound.HPLC-MS (ammonium acetate) [M+H] ⁺=375.3.

(R, S)-6-fluoro-7-methyl isophthalic acid-[2-methyl-3-(4-propoxyl group piperidyl-1)-propyl group-3,4-dihydro-1H-quinoline Quinoline-2-ketone (107LH94-2)

[0335] at N ₂Add the 6-fluoro-7-methyl-3 that is dissolved among the dried DMF (1mL) in the downhill reaction flask, and 4-dihydro-1H-quinoline-2-one-(0.150g, 0.84mmol).(contain 60% in the oil, 0.038g 0.92mmol), and at room temperature stirs 30min to add NaH.Add then (R, S)-(0.144g 0.84mmol), at room temperature stirs 20h to 1-bromo-3-chloro-2-methylpropane then.The quencher of reactant mixture water, product extracts with EtOAc.Merge organic layer, use Na ₂SO ₄Drying is filtered, and concentrates.Crude product is dissolved in to be done among the DMF (2mL), add then 4-propoxyl group piperidines (0.086g, 0.6mmol), NaI (0.150g, 1.0mmol) and K ₂CO ₃(0.138g 1.0mmol), and shakes 20h under 100 ℃.The quencher of reactant mixture water, product extracts with EtOAc.Merge organic layer, use Na ₂SO ₄Drying is filtered, and concentrates.Residue cation exchange CC purification, quick then CC (SiO ₂EtOAc) purification obtains title compound (107LH94-2) (0.033g, gross production rate 10%). ¹H?NMR(CH ₃OD)δ7.02(d，J＝6.8Hz，1H)，6.91(d，J＝9.6Hz，1H)，3.95(d，J＝7.2Hz，2H)，3.41(t，J＝6.6Hz，2H)，3.33-3.25(m，1H)，2.84(brt，J＝7.4Hz)，2.79-2.71(m，1H)，2.67-2.51(m，3H)，2.28-1.98(m，8H)，1.92-1.83(m，2H)，1.60-1.48(m，4H)，0.91(t，J＝7.6Hz，3H)，0.85(d，J＝6.4Hz，3H)； ¹³C?NMR(CH ₃OD)δ171.7，157.2(d，J＝241Hz)，135.1(d，J＝3Hz)，126.9(d，J＝8Hz)，123.1(d，J＝18Hz)，114.3(d，J＝24Hz)，75.2，69.5，52.1，51.7，45.5，31.6，31.3，29.0，24.6，23.1，15.9，13.5，13.3，9.8。

[0336] product is dissolved in acetone, adds the oxalic acid (1.1 equivalent) that is dissolved in acetone.Filter the crystal that forms, use washing with acetone, obtain the oxalates (0.036g) of title compound.HPLC-MS (ammonium acetate) [M+H] ⁺=377.3.

1-[3-(propyl group of 4-butyl-piperidyl-1-)]-6-fluoro-5-methyl-3,4-dihydro-1H-quinoline-2-one- (107LH95-1)

[0337] at N ₂Add the 6-fluoro-5-methyl-3 that is dissolved among the dried DMF (0.5mL) in the downhill reaction flask, and 4-dihydro-1H-quinoline-2-one-(0.090g, 0.50mmol).(contain 60% in the oil, 0.023g 0.55mmol), and at room temperature stirs 30min to add NaH.(0.079g 0.50mmol), at room temperature stirs 20h then to add 3-chloro-propyl iodide then.The quencher of reactant mixture water, product extracts with EtOAc.Merge organic layer, use Na ₂SO ₄Drying is filtered, and concentrates.Crude product is dissolved among the MeCN (2mL), add then the 4-butyl piperidine (0.085g, 0.6mmol), NaI (0.150g, 1.0mmol) and K ₂CO ₃(0.138g 1.0mmol), and shakes 20h under 50 ℃.The quencher of reactant mixture water, product extracts with EtOAc.Merge organic layer, use Na ₂SO ₄Drying is filtered, and concentrates.Residue is used quick CC (SiO then with cation exchange CC purification ₂EtOAc) purification obtains title compound (107LH95-1) (0.059g, gross production rate 33%). ¹H?NMR(CH ₃OD)δ7.02(dd，J＝4.8，9.2Hz，1H)，6.98-6.92(m，1H)，3.95(brt，J＝7.4Hz，2H)，2.92-2.82(m，4H)，2.59-2.52(m，2H)，2.39-2.32(m，2H)，2.00(d，J＝1.6Hz，3H)，1.97-1.75(m，4H)，1.66(brd，10.8Hz，2H)，1.35-1.12(m，9H)，0.89(t，J＝6.4Hz)； ¹³C?NMR(CH ₃OD)δ?170.9，157.6(d，J＝240Hz)，135.4(d，J＝3Hz)，128.1(d，J＝4Hz)，122.7(d，J＝18Hz)，114.2(d，J＝8Hz)，112.9，(d，J＝25Hz)，55.9，53.9，40.6，36.2，35.7，31.9，30.9，28.9，24.4，22.8，21.4(br)，13.2，9.7(br)。

[0338] product is dissolved in acetone, adds the oxalic acid (1.1 equivalent) that is dissolved in acetone.Filter the crystal that forms, use washing with acetone, obtain the oxalates (0.058g) of title compound.HPLC-MS (ammonium acetate) [M+H] ⁺=361.3.

6-fluoro-5-methyl isophthalic acid-[3-(propyl group of 4-propoxyl group piperidyl-1-)]-3,4-dihydro-1H-quinoline-2-one- (107LH95-2)

[0339] at N ₂Add the 6-fluoro-5-methyl-3 that is dissolved among the dried DMF (0.5mL) in the downhill reaction flask, and 4-dihydro-1H-quinoline-2-one-(0.090g, 0.50mmol).(contain 60% in the oil, 0.023g 0.55mmol), and at room temperature stirs 30min to add NaH.(0.079g 0.50mmol), at room temperature stirs 20h then to add 3-chloro-propyl iodide then.The quencher of reactant mixture water, product extracts with EtOAc.Merge organic layer, use Na ₂SO ₄Drying is filtered, and concentrates.Crude product is dissolved among the MeCN (2mL), add then 4-propoxyl group piperidines (0.086g, 0.6mmol), NaI (0.150g, 1.0mmol) and K ₂CO ₃(0.138g 1.0mmol), and shakes 20h under 50 ℃.The quencher of reactant mixture water, product extracts with EtOAc.Merge organic layer, use Na ₂SO ₄Drying is filtered, and concentrates.Residue is used quick CC (SiO then with cation exchange CC purification ₂EtOAc) purification obtains title compound (107LH95-2) (0.074g, gross production rate 41%). ¹H?NMR(CH ₃OD)δ7.03(dd，J＝4.8，9.2Hz，1H)，6.99-6.92(m，1H)，3.98(brt，J＝7.4Hz，2H)，3.46-3.38(m，3H)，2.95-2.84(m，4H)，2.64-2.42(m，6H)，2.20(d，J＝2.0Hz，3H)，1.98-1.83(m，4H)，1.72-1.30(m，4H)，0.92(t，J＝7.4Hz，3H)； ¹³C?NMR(CH ₃OD)δ171.1，157.7(d，J＝240Hz)，135.4(d，J＝3Hz)，128.1(d，J＝4Hz)，122.8(d，J＝18Hz)，114.1(d，J＝9Hz)，113.0(d，J＝25Hz)，73.1，69.7，55.0，50.3，40.3，30.8，29.9，23.9，23.1，22.7，21.4，9.8(br)。

[0340] product is dissolved in acetone, adds the oxalic acid (1.1 equivalent) that is dissolved in acetone.Filter the crystal that forms, use washing with acetone, obtain the oxalates (0.067g) of title compound.HPLC-MS (ammonium acetate) [M+H] ⁺=363.3.

(R)-and 1-[3-(4-butyl piperidine base-1)-2-methyl-propyl-3,4-dihydro-1H-quinoline-2-one- (107LH47-A)

[0341] in the 4mL bottle, adds (the S)-1-(3-iodo-2-methyl-propyl)-3 that is dissolved among the MeCN (2mL), 4-dihydro-1H-quinoline-2-one-(122LH18) (0.329g, 1.0mmol) and the 4-butyl piperidine (0.283g 2.0mmol), and shakes 20h under 60 ℃.Concentrated reaction mixture, product is with quick CC (SiO ₂EtOAc, EtOAc/MeOH 4: 1) purification, obtain title compound (107LH47-A) (0.186g, 54%). ¹H?NMR(CD ₃OD)δ7.26-7.19(m，3H)，7.04-7.00(m，1H)，2.93-2.88(m，3H)，2.77(d，J＝10.4Hz，2H)，2.62-2.58(m，2H)，2.29-2.06(m，3H)，1.93-1.86(m，2H)，1.68-1.62(m，2H)，1.31-1.22(m，9H)，0.91-0.86(m，2CH ₃)； ¹³C?NMR(CD ₃OD)δ173.2，140.3，129.1，128.5，128.4，124.4，166.9，64.9，56.0，55.6，37.5，36.9，33.4，33.3，32.9，30.1，30.1，26.2，24.0，17.2，14.4。

[0342] product is dissolved in acetone, adds the oxalic acid that is dissolved in acetone.Filter the crystal that forms, use washing with acetone, obtain the oxalates (0.222g) of title compound.HPLC-MS (ammonium acetate) [M+H] ⁺=343.33.

(R)-and 1-[2-methyl-3-(propyl group of 4-propoxyl group piperidyl-1-)]-3,4-dihydro-1H-quinoline-2-one- (107LH48)

[0343] in the 4mL bottle, adds (the S)-1-(3-iodo-2-methyl-propyl)-3 that is dissolved among the MeCN (2mL), 4-dihydro-1H-quinoline-2-one-(122LH18) (0.493g, 1.5mmol) and 4-propoxyl group piperidines (0.430g 3.0mmol), and shakes 20h under 60 ℃.The quencher of reactant mixture water, with the ammonium hydroxide alkalization, product extracts with EtOAc.Merge organic layer, use Na ₂SO ₄Drying is filtered, and concentrates.Product is with quick CC (SiO ₂EtOAc, EtOAc/MeOH 4: 1) purification, obtain title compound (107LH48) (0.197g, 38%). ¹H?NMR(CD ₃OD)δ7.26-7.19(m，3H)，7.03-6.98(m，1H)，3.96(d，J＝7.0Hz，2H)，3.40(t，J＝6.7Hz，2H)，2.90-2.86(m，2H)，2.74-2.71(m，1H)，2.65-2.54(m，3H)，2.26-1.99(m，6H)，1.87-1.84(m，2H)，1.59-1.49(m，4H)，0.91(t，J＝7.4Hz，CH ₃)，0.85(d，J＝6.6Hz，CH ₃)； ¹³CNMR(CD ₃OD)δ173.0，140.3，129.1，128.4，128.4，124.3，116.8，76.3，70.7，64.5，53.2，52.8，32.9，32.4，32.4，30.3，26.2，24.3，17.1，11.0。

[0344] product is dissolved in acetone, adds the oxalic acid that is dissolved in acetone.Filter the crystal that forms, use washing with acetone, obtain the oxalates (0.189g) of title compound.HPLC-MS (ammonium acetate) [M+H] ⁺=345.31.

(R)-and 1-[3-(4-butylidene piperidyl-1)-2-methyl-propyl]-3,4-dihydro-1H-quinoline-2-one- (107LH53)

[0345] in the 4mL bottle, adds (the S)-1-(3-iodo-2-methyl-propyl)-3 that is dissolved among the MeCN (2mL), 4-dihydro-1H-quinoline-2-one-(122LH18) (0.169g, 0.51mmol) and 4-butylidene piperidines (0.200g 1.4mmol), and shakes 20h under 40 ℃.The quencher of reactant mixture water, with the ammonium hydroxide alkalization, product extracts with EtOAc.Merge organic layer, use Na ₂SO ₄Drying is filtered, and concentrates.Product is with quick CC (SiO ₂Normal heptane/EtOAc 4: 1) purification obtains title compound (107LH53) (0.116g, 67%). ¹H??NMR(CD ₃OD)δ7.23-7.18(m，3H)，7.02-6.98(m，1H)，5.11(t，J＝7.4Hz，1H)，3.98(d，J＝6.8Hz，2H)，2.89-2.85(m，2H)，2.61-2.56(m，2H)，2.40-2.35(m，2H)，3.32-2.04(m，11H)，1.98-1.92(m，2H)，1.36-1.29(m，2H)，0.90-0.85(m，2CH ₃)； ¹³C?NMR(CD ₃OD)δ173.0，140.3，137.1，129.1，128.4，128.4，124.3，123.7，116.9，64.6，57.4，56.6，46.5，37.0，32.9，30.2，30.1，29.1，26.3，24.2，17.2，14.1。

[0346] product is dissolved in acetone, adds the oxalic acid that is dissolved in acetone.Filter the crystal that forms, use washing with acetone, obtain the oxalates (0.130g) of title compound.HPLC-MS (ammonium acetate) [M+H] ⁺=341.33.

(R)-and 1-[3-(3-butyl-8-azabicyclo [3.2.1] octyl group-8)-2-methyl-propyl]-3,4-dihydro-1H-quinoline -2-ketone (107LH54)

[0347] in the 4mL bottle, adds (the S)-1-(3-iodo-2-methyl-propyl)-3 that is dissolved among the MeCN (0.5mL), 4-dihydro-1H-quinoline-2-one-(122LH18) (0.185g, 0.56mmol) and 3-butyl-8-azabicyclo [3.2.1] octane (0.100g, 0.60mmol), and under 40 ℃, shake 20h.The quencher of reactant mixture water, with the ammonium hydroxide alkalization, product extracts with EtOAc.Merge organic layer, use Na ₂SO ₄Drying is filtered, and concentrates.Product is with quick CC (SiO ₂Normal heptane/EtOAc 4: 1) purification obtains title compound (107LH54) (0.063g, 30%). ¹H?NMR(CD ₃OD)δ7.29-7.19(m，3H)，7.03-6.99(m，1H)，4.03-4.00(m，2H)，3.14-3.13(m，1H)，3.07-3.05(m，1H)，2.90-2.86(m，2H)，2.62-2.57(m，2H)，2.28-2.19(m，2H)，1.97-1.82(m，3)，1.58-1.42(m，5H)，1.34-1.15(m，8H)，0.90-0.87(m，6H)； ¹³C?NMR(CD ₃OD)δ173.1，140.3，129.1，128.4，128.3，124.3，117.2，62.2，61.2，58.2，46.5，39.0，38.0，32.9，32.1，30.3，29.1，27.8，27.3，26.3，24.0，17.1，14.5。

[0348] product is dissolved in acetone, adds the oxalic acid that is dissolved in acetone.Filter the crystal that forms, use washing with acetone, obtain the oxalates (0.064g) of title compound.HPLC-MS (ammonium acetate) [M+H] ⁺=369.34.

(R)-1-[2-methyl-3-(propyl group-3 of 3-amyl group-8-azabicyclo [3.2.1] octyl group-8-), 4-dihydro-1H-quinoline -2-ketone (107LH55)

[0349] in the 4mL bottle, adds (the S)-1-(3-iodo-2-methyl-propyl)-3 that is dissolved among the MeCN (0.5mL), 4-dihydro-1H-quinoline-2-one-(122LH18) (0.185g, 0.56mmol) and 3-amyl group-8-azabicyclo [3.2.1] octane (0.112g, 0.62mmol), and under 40 ℃, shake 20h.The quencher of reactant mixture water, with the ammonium hydroxide alkalization, product extracts with EtOAc.Merge organic layer, use Na ₂SO ₄Drying is filtered, and concentrates.Product is with quick CC (SiO ₂Normal heptane/EtOAc 4: 1) purification obtains title compound (107LH55) (0.075g, 35%). ¹H?NMR(CD ₃OD)δ7.28-7.18(m，3H)，7.01(t，J＝7.2Hz，1H)，4.03(d，J＝7.0Hz，2H)，3.11-3.04(m，2H)，2.90-2.85(m，2)，2.64-2.56(m?2H)，2.28-2.11(m，4H)，1.97-1.84(m，3H)，1.66-1.54(m，3H)，1.42-1.21(m，10H)，0.90-0.85(m，2CH ₃)； ¹³C?NMR(CD ₃OD)δ173.1，140.3，129.1，128.4，128.3，124.3，117.1，61.4，60.2，58.3，46.4，39.5，37.1，37.0，33.1，32.9，32.2，29.5，29.4，28.5，27.9，26.3，23.7，17.1，14.4。

[0350] product is dissolved in acetone, adds the oxalic acid that is dissolved in acetone.Filter the crystal that forms, use washing with acetone, obtain the oxalates (0.054g) of title compound.HPLC-MS (ammonium acetate) [M+H] ⁺=383.35.

1-[3-(propyl group of 4-butyl piperidine base-1-)]-1H-quinoline-2-one-(092LH70-A)

[0351] in the 7mL bottle, add 1-(3-chloropropyl)-1H-quinoline-2-one-(0.450g, 2.0mmol), K ₂CO ₃(0.34g, 2.5mmol), KI (0.42g, 2.5mmol), the 4-butyl piperidine (0.30g, 2.1mmol) and dried CH ₃CN (3mL).Mixture shakes 60h under 50 ℃, use EtOAc (50mL) dilution subsequently, water (50mL) washing.(2 * 50mL) extract water with EtOAc.Merge organic facies, use Na ₂SO ₄Drying is filtered concentrating under reduced pressure.Residue is with quick CC (SiO ₂EtOAc/MeOH 4: 1) purification with preparation property RP-HPLC purification, obtains title compound (0.32g, 49%) then. ¹H?NMR(CD ₃OD)δ7.88(d，J＝9.6Hz)，7.68(brd，J＝8.0Hz)，7.65-7.61(m，2H)，7.33-7.25(m，1H)，6.64(d，9.6Hz)，4.39-4.32(m，2H)，2.95-2.86(m，2H)，2.50-2.43(m，2H)，2.01-1.86(m，4H)，1.71-1.62(m，2H)，1.35-1.12(m，9H)，0.89(t，J＝6.6Hz)； ¹³C?NMR(CD ₃OD)δ163.1，140.4，139.0，131.1，129.2，122.6，121.4，120.3，114.7，55.8，53.9，40.6，36.2，35.7，32.0，28.9，24.7，22.8，13.2。

[0352] product is dissolved in acetone, adds the oxalic acid (1.1 equivalent) that is dissolved in acetone.Filter the crystal that forms, use washing with acetone, obtain the oxalates (0.356g) of title compound.HPLC-MS (ammonium acetate) [M+H] ⁺=327.3.

1-[3-(propyl group of 4-propoxyl group piperidyl-1-)]-1H-quinoline-2-one-(092LH69)

[0353] in the 4mL bottle, add 1-(3-chloropropyl)-1H-quinoline-2-one-(0.069g, 0.31mmol), K ₂CO ₃(0.069g, 0.50mmol), KI (0.083g, 0.50mmol), 4-propoxyl group piperidines (0.050g, 0.35mmol) and dried CH ₃CN (2mL).Under 50 ℃, shake mixture 24h, water (25mL) and EtOAc (25mL) dilution subsequently.Separate each phase, (2 * 50mL) extract water with EtOAc.Merge organic facies, use Na ₂SO ₄Drying is filtered concentrating under reduced pressure.Residue is with quick CC (SiO ₂EtOAc/MeOH 4: 1) purification with preparation property RP-HPLC purification, obtains title compound (0.060g, 59%) then. ¹H NMR (CD ₃OD) δ 7.85 (d, J=9.4Hz, 1H), 7.65 (brd, J=7.2Hz, 1H), 7.63 (m, 2H), 7.29-7.22 (m, 1H), 6.62, (d, J=9.4Hz), and 4.36-4.29 (m, 1H), 3.38 (t, J=6.6Hz, 2H), and 3.34-3.24 (m, 1H), 2.78-2.69 (m, 2H), 2.48-2.41 (m, 2H), 2.18-2.09 (m, 2H), 1.94-1.82 (m, 4H), 1.59-1.47 (m, 4H), 0.90 (t, J=7.4Hz); ¹³CNMR (CD ₃OD) δ 162.0,140.3, and 139.0,131.1,129.2,122.6,121.4,120.3,114.7,74.7,69.5,55.4,51.0,40.6,31.0,24.9,32.1,9.9; HPLC-MS (ammonium acetate) [M+H] ⁺=329.3.

1-[3-(propyl group of 4-butyl piperidine base-1-)]-6-fluoro-1H-quinoline-2-one-(107LH22)

[0354] in the 4mL bottle, add 6-fluoro-1H-quinoline-2-one-(00.56g, 0.34mmol), do DMF (2mL) and NaH (contain 60% in the oil, 0.015g, 0.34mmol).At N ₂In the 1h that under room temperature, stirs the mixture, (34 μ l 0.34mmol), at room temperature shake mixture 20h then to add 1-bromo-3-chloropropane subsequently.Reaction is diluted with ether (25mL), water (15mL) washing.Na is used in organic facies water (15mL) and saline (15mL) washing ₂SO ₄Drying, concentrating under reduced pressure.Use CH ₃CN (2mL) dilution oily residue, add KI (0.083g, 0.50mmol), K ₂CO ₃(0.069g, 0.50mmol) and the 4-butyl piperidine (0.048g, 0.34mmol).Under 50 ℃, shake mixture 72h, use EtOAc (25mL) dilution then, water (15mL) washing.(2 * 25mL) waters merge organic facies, use Na in extraction ₂SO ₄Drying, concentrating under reduced pressure.Residue is used quick CC (SiO then with cation exchange CC purification ₂EtOAc/MeOH 4: 1) purification obtains title compound (0.034g, 29%). ¹H NMR (CD ₃OD) δ 7.90 (d, J=9.2Hz, 1H), 7.69 (dd, J=4.0,8.8Hz, 1H), and 7.50-7.41 (m, 2H), 6.72 (d, J=8.8Hz, 1H), 4.41 (t, J=6.8Hz, 2H), 3.02-2.95 (m, 2H), 2.65-2.60 (m, 2H), 2.19-2.08 (m, 2H), 1.91-1.82 (m, 4H), 1.53-1.21 (m, 9H), 0.90 (t, J=7.0Hz); ¹³C NMR (CD ₃OD) δ 169.9,158.4 (d, J=242Hz), 139.8 (d, J=3Hz), 134.4 (d, J=2Hz), 122.5 (d, J=9Hz), 121.6,119.9 (d, J=24Hz), 116.8 (d, J=8Hz), 113.9 (d=23Hz), 54.4,53.0,40.1,34.5,34.1,30.1,28.7,23.3,22.6,13.2; HPLC-MS (ammonium acetate) [M+H] ⁺=345.3.

1-[3-(propyl group of 4-butyl piperidine base-1-)]-6-methyl isophthalic acid H-quinoline-2-one-(107LH32-A)

[0355] in the 4mL bottle, add 6-methyl isophthalic acid H-quinoline-2-one-(0.110g, 0.71mmol), do DMF (2mL) and NaH (contain 60% in the oil, 0.031g, 0.78mmol).At N ₂In shake mixture 1h, add subsequently 1-bromo-3-chloropropane (70 μ l, 0.71mmol).20h is at room temperature shaken in reaction, is poured in the ether (25mL) water (15mL) washing then.Ether phase water (15mL) and saline (15mL) washing.Organic facies Na ₂SO ₄Drying, concentrating under reduced pressure.Use CH ₃CN (2mL) dilutes residue, add KI (0.160g, 1.0mmol), K ₂CO ₃(0.140g, 1.0mmol) and the 4-butyl piperidine (0.100g, 0.71mmol).Under 50 ℃, shake mixture 72h, topple over then among the EtOAc (25mL) and water (15mL).(2 * 25mL) waters merge organic facies, use Na in extraction ₂SO ₄Drying, concentrating under reduced pressure.Residue is with quick CC (SiO ₂EtOAc/MeOH 4: 1) purification with preparation property RP-HPLC purification, obtains title compound (0.058g, 23%) then. ¹H NMR (CD ₃OD) δ 7.78 (d, J=9.2Hz, 1H), 7.52-7.40 (m, 3H), 6.60 (d, J=9.2Hz, 1H), 4.3 (t, J=7.6Hz, 2H), 2.92-2.2.85 (m, 2H), 2.50-2.39 (m, 2H), 2.39 (s, 3H), 1.99-1.84 (m, 4H), 1.69-1.61 (m, 2H), 1.35-1.11 (m, 9H), 0.88 (t, J=6.8Hz); ¹³C NMR (CD ₃OD) δ 162.9,140.1, and 137.0,132.5,132.3,128.8,121.4,120.2,114.6,55.8,53.9,40.6,36.2,35.7,32.0,28.9,24.8,22.8,19.4,13.3; HPLC-MS (ammonium acetate) [M+H] ⁺=341.3.

1-[3-(4-butyl piperidine base-1) propyl group]-7-fluoro-1H-quinoline-2-one-(107LH33-A)

[0356] in the 4mL bottle, add 7-fluoro-1H-quinoline-2-one-(0.032g, 0.19mmol), NaH (contain 60% in the oil, 8.7mg, 0.21mmol) and dried DMF (2.5mL).At room temperature shake mixture 1h, (20 μ l 0.19mmol), at room temperature shake reaction and spend the night to add 1-bromo-3-chloropropane then.Mixture dilutes with ether (25mL), water (15mL) washing, ether phase water (15mL) and saline (15mL) washing.Organic facies Na ₂SO ₄Drying, concentrating under reduced pressure.Use CH ₃CN (2mL) dilution oily residue adds in the solution that obtains: and KI (0.050g, 0.30mmol), K ₂CO ₃(0.041g, 0.30mmol) and the 4-butyl piperidine (0.028g, 0.20mmol).Under 50 ℃, shake mixture 72h, topple over then among the EtOAc (25mL) and water (15mL).(2 * 25mL) waters merge organic facies, use Na in extraction ₂SO ₄Drying, concentrating under reduced pressure.Residue is with quick CC (SiO ₂EtOAc/MeOH 4: 1) purification with preparation property RP-HPLC purification, obtains title compound (7.0mg, 11%) then. ¹HNMR (CD ₃OD) δ 7.89 (d, J=9.6Hz, 1H), 7.73 (dd, J=6.2,8.6Hz, 1H), 7.47 (dd, J=2.4,11.6Hz, 1H), 7.08 (dt, J=2.4,8.6Hz, 1H), 6.60 (d J=9.6Hz, 1H), 4.33 (t, J=7.6Hz, 2H), 2.98-2.00 (m, 2H), 2.50-2.42 (m, 2H), 2.05-1.86 (m, 4H), 1.55-1.64 (m, 2H), 1.36-1.15 (m, 9H), 0.90 (t, J=6.8Hz); ¹³C NMR (CD ₃OD) δ 164.7 (d, J=248), 163.2,140.9 (br), 139.9,131.4 (d, J=10Hz), 119.3 (d, J=3Hz), 118.1 (br), 110.6 (d, J=23Hz), 101.6 (d, J=28Hz), 55.5,53.9,41.0,36.8,35.6,31.9,28.9,24.5,22.7,13.2; HPLC-MS (ammonium acetate) [M+H] ⁺=345.3.

1-[3-(propyl group of 4-butyl piperidine base-1-)]-6-methoxyl group-1H-quinoline-2-one-(107LH37-A)

[0357] in the 4mL bottle, add 6-methoxyl group-1H-quinoline-2-one-(0.032g, 0.18mmol), do DMF (2mL) and NaH (contain 60% in the oil, 8mg, 0.20mmol), subsequently at N ₂In the 45min that under 45 ℃, stirs the mixture, (18 μ l 0.18mmol), shake mixture overnight under 30 ℃ to add 1-bromo-3-chloropropane then.With ether (25mL) diluting reaction, water (15mL) washing, Na is used in ether phase water (15mL) and saline (15mL) washing ₂SO ₄Drying, concentrating under reduced pressure.Use CH ₃CN (3mL) dilution oily residue, add KI (0.080g, 0.50mmol), K ₂CO ₃(0.070g, 0.50mmol) and the 4-butyl piperidine (0.028g, 0.20mmol).Under 50 ℃, shake mixture 48h, use EtOAc (25mL) dilution then, water (15mL) washing.(2 * 25mL) waters merge organic facies, use Na in extraction ₂SO ₄Drying, concentrating under reduced pressure.Residue obtains title compound (0.028g, 44%) with preparation property RP-HPLC purification. ¹H NMR (CD ₃OD) δ 7.85 (d, J=9.6Hz, 1H), 7.56 (d, J=9.2Hz, 1H), 7.26 (dd, J=2.8,9.6Hz, 1H), 7.19 (d, J=2.8Hz, 1H), 6.65 (d, J=9.6Hz, 1H), 4.34 (t, J=7.2Hz, 2H), 3.85 (s, 3H), 3.07-2.98 (m, 2H), 2.64-2.58 (m, 2H), and 2.1 9-2.10 (m, 2H), 2.04-1.94 (m, 2H), 1.76-1.66 (m, 2H), 1.35-0.96 (m, 9H), 0.89 (t, J=6.8Hz); ¹³C NMR (CD ₃OD) δ 162.7,155.5, and 140.1,133.3,122.3,120.6,120.1,116.1,110.5,55.3,55.0,53.6,40.5,36.0,35.2,31.4,28.8,24.4,22.7,13.2; HPLC-MS (ammonium acetate) [M+H] ⁺=357.3.

1-[3-(propyl group of 4-butyl piperidine base-1-)]-6-chloro-1H-quinoline-2-one-(107LH38-A)

[0358] in the 4mL bottle, add 6-chloro-1H-quinoline-2-one-(107LH35) (0.085g, 0.47mmol), do DMF (3mL) and NaH (contain 60% in the oil, 0.023g, 0.56mmol), at N ₂In the 45min that under room temperature, stirs the mixture.(18 μ l 0.18mmol), at room temperature shake mixture overnight, and reaction is diluted with ether (25mL), water (15mL) washing to add 1-bromo-3-chloropropane subsequently.Ether is used saline (15mL) washing mutually, uses Na ₂SO ₄Drying, concentrating under reduced pressure.With dried CH ₃CN (2mL) dilution oily residue, add KI (0.170g, 1.0mmol), K ₂CO ₃(0.140g, 1.0mmol) and the 4-butyl piperidine (0.071g, 0.50mmol).Under 50 ℃, shake mixture 24h, use EtOAc (25mL) dilution then, water (15mL) washing.(2 * 25mL) waters merge organic facies, use Na in extraction ₂SO ₄Drying, concentrating under reduced pressure.Residue obtains title compound (32mg, 89 μ mol, 19%) with preparation property RP-HPLC purification. ¹H NMR (CD ₃OD) δ 7.80 (d, J=9.2Hz, 1H), 7.66 (brs, 1H), 7.60-7.51 (m, 2H), 6.65 (d, J=9.6Hz, 1H), 5.30 (t, J=7.6Hz, 2H), 3.09-2.95 (m, 2H), 2.68-2.57 (m, 2H), 2.24-2.06 (m, 2H), 2.00-1.90 (m, 2H), and 1.75-1.64 (m, 2H), 1.32-1.12 (m, 9H), 0.84 (t, 6.4Hz, 3H); ¹³C NMR (CD ₃OD) δ 162.6,139.2, and 137.4,130.8,128.0,127.8,122.4,121.5,116.3,55.0,53.3,40.3,35.7,34.8,31.0,28.6,23.9,22.5,13.0; HPLC-MS (ammonium acetate) [M+H] ⁺=361.3.

1-[3-(propyl group of 4-butyl piperidine base-1-)]-5-methyl isophthalic acid H-quinoline-2-one-(107LH45)

[0359] adding is dissolved in CH in the 4mL bottle ₃1-among the CN (2mL) (3-chloropropyl)-5-methyl isophthalic acid H-quinoline-2-one-(0.053g, 0.23mmol), KI (0.083g, 0.5mmol), K ₂CO ₃(0.069g, 0.50mmol) and the 4-butyl piperidine (50 μ l, 0.30mmol).Mixture shakes 72h under 50 ℃, use EtOAc (25mL) dilution then, water (15mL) washing.(2 * 25mL) waters merge organic facies, use Na in extraction ₂SO ₄Drying, concentrating under reduced pressure.Residue is with quick CC (SiO ₂EtOAc/MeOH1: 4) purification obtains title compound (0.058g, 74%). ¹H NMR (CD ₃OD) δ 8.13 (d, J=9.8Hz, 1H), 7.56-7.46 (m, 2H), 7.15 (brd, 6.8Hz, 2H), 6.67 (d, J=9.8Hz, 1H), 4.38 (t, J=7.2Hz, 2H), 3.10-3.03 (m, 2H), 2.68-2.61 (m, 2H), 2.57 (s, 3H), 2.25-2.15 (m, 2H), and 2.04-1.95 (m, 2H), 1.78-1.69 (m, 2H), 1.36-1.16 (m, 9H), 0.89 (t, J=7.0Hz, 3H); ¹³C NMR (CD ₃OD) δ 162.3,138.7, and 136.6,136.2,130.4,123.6,119.4,118.9,112.4,54.7,52.9,39.9,35.3,34.5,30.7,28.2,23.7,22.1,17.3,12.6; HPLC-MS (ammonium acetate) [M+H] ⁺=341.3.

1-[3-(propyl group of 4-butyl-piperidyl-1-)]-7-methyl isophthalic acid H-quinoline-2-one-(107LH46-A)

[0360] adding is dissolved in CH in the 4mL bottle ₃1-among the CN (2mL) (3-chloro-propyl group)-7-methyl isophthalic acid H-quinoline-2-one-107LH40 (0.130g, 0.56mmol), KI (0.170g, 1.0mmol), K ₂CO ₃(0.140g, 1.0mmol) and the 4-butyl piperidine (100 μ l, 0.60mmol).Mixture shakes 72h under 50 ℃, be poured over then in EtOAc (25mL) and the water (15mL).(2 * 25mL) waters merge organic facies, use Na in extraction ₂SO ₄Drying, concentrating under reduced pressure.Residue is with quick CC (SiO ₂EtOAc/MeOH 1: 4) purification obtains title compound (0.017g, 6%). ¹H NMR (CD ₃OD) δ 7.84 (d, J=9.4Hz), 7.56 (d, J=8.0Hz, 1H), 7.43 (brs, 1H), 7.14 (brd, J=8Hz, 1H), 6.58 (d, J=9.4Hz), 4.36 (d, J=7.2Hz, 2H), 3.02-2.95 (m, 2H), 2.57-2.48 (m, 2H), 2.51 (s, 3H), and 2.09-1.91 (m, 4H), 1.75-1.65 (m, 2H), 1.36-1.16 (m, 9H), 0.89 (t, J=6.8Hz, 3H); ¹³C NMR (CD ₃OD) δ 163.3,142.2, and 140.3,139.1,129.1,124.1,119.3,119.0,114.7,55.6,53.8,40.4,36.1,35.5,31.8,28.9,24.6,22.7,21.1,13.2; HPLC-MS (ammonium acetate) [M+H] ⁺=341.3.

(R)-1-[3-(4-butyl piperidine base-1)-2-methyl-propyl]-1H-quinoline-2-one-(107LH52)

[0361] in the 4mL bottle, add (S)-1-(3-iodo-2-methyl-propyl group)-1H-quinoline-2-one-crude product (0.66g), 4-butyl piperidine (0.43g, 3.0mmol) and dried CH ₃CN (1mL).Mixture shakes 72h under 50 ℃, be poured over then in EtOAc (50mL) and the water (25mL).(2 * 25mL) waters merge organic facies, use Na in extraction ₂SO ₄Drying, concentrating under reduced pressure.Residue is with quick CC (SiO ₂EtOAc/MeOH 1: 4) purification is used cation exchange CC purification then, obtains title compound (0.300g, 44%). ¹H?NMR(CD ₃OD)δ7.88(d，J＝9.2Hz，1H)，7.73-7.66(m，2H)，7.61(t，J＝8.0Hz，1H)，7.29(t，J＝7.4Hz，1H)，6.65(d，J＝9.2Hz，1H)，4.42-4.26(m，2H)，2.90(brd，J＝11.4Hz，1H)，2.74(brd，J＝11.4Hz，1H)，2.40-2.16(m，3H)，1.94-1.78(m，2H)，1.64-1.54(m，2H)，1.35-1.00(m，9H)，0.96-0.85(m，6H)； ¹³C?NMR(CD ₃OD)δ163.7，140.2，139.5，130.8，129.1，122.5，121.4，120.4，115.3，64.0，55.1，54.2，46.8，36.3，35.8，32.4，32.3，29.8，28.9，22.8，16.1，13.2。

[0362] product is dissolved in acetone, adds the hydroxymalonic acid (1.1 equivalent) that is dissolved in acetone.Filter the crystal that forms, use washing with acetone, obtain the oxalates (0.277g) of title compound.HPLC-MS (ammonium acetate) [M+H] ⁺=341.3.

(R)-1-[2-methyl-3-(4-propoxyl group piperidyl-1)-propyl group]-1H-quinoline-2-one-(107LH65)

[0363] in the 4mL bottle, add (S)-1-(3-iodo-2-methyl-propyl)-1H-quinoline-2-one-crude product (0.190g), 4-propoxyl group piperidines (0.137g, 0.96mmol) and dried CH ₃CN (2.5mL).Mixture shakes 24h under 50 ℃, use cation exchange CC purification then, the quick CC (SiO of reuse ₂EtOAc/MeOH 1: 4) purification obtains title compound (0.051g, 17%). ¹H?NMR(CD ₃OD)δ7.85(d，J＝9.6Hz)，7.70-7.63(m，2H)，7.60(brt，J＝7.8Hz，1H)，7.26(brt，7.6Hz)，6.63(d，J＝9.6Hz，1H)，4.39-4.23(m，2H)，3.37(t，J＝6.6Hz)，3.28-3.18(m，1H)，2.77-2.69(m，1H)，2.64-2.58(m，1H)，2.35(dd，J＝8.4，12.0Hz)，2.51-2.21(m，1H)，2.18(dd，J＝4.8，12.0Hz)，2.13-2.04(m，1H)，2.00-1.92(m，1H)，1.84-1.75(m，2H)，1.58-1.32(m，4H)，0.95-0.85(m，6H)； ¹³C?NMR(CD ₃OD)δ163.7，140.2，139.5，130.8，129.2，12.5，121.4，120.4，115.2，75.3，69.5，63.6，52.3，51.5，46.8，31.4，31.3，30.0，23.1，16.1，9.8。

[0364] product is dissolved in acetone, adds the oxalic acid (1.1 equivalent) that is dissolved in acetone.Filter the crystal that forms, use washing with acetone, obtain the oxalates (0.032g) of title compound.HPLC-MS (ammonium acetate) [M+H] ⁺=343.3.

1-[3-(propyl group of 4-allyloxy piperidyl-1-)]-1H-quinoline-2-one-(107LH85)

[0365] in the 4mL bottle, add 1-(3-chloropropyl)-1H-quinoline-2-one-(0.130g, 0.6mmol), NaI (0.225g, 1.5mmol), K ₂CO ₃(0.210g, 1.5mmol), 4-allyloxy piperidines (0.085g, 0.60mmol) and dried CH ₃CN (1mL).Mixture shakes 72h under 40 ℃, be poured over then in EtOAc (25mL) and the water (15mL).(2 * 25mL) waters merge organic facies, use Na in extraction ₂SO ₄Drying, concentrating under reduced pressure.Residue is with quick CC (SiO ₂EtOAc/MeOH 4: 1) purification is used cation exchange CC purification then, obtains title compound (0.140g, 70%). ¹HNMR(CD ₃OD)δ7.81(d，J＝9.6Hz，1H)，7.64-7.55(m，3H)，7.27-7.21(m，1H)，6.61(d，J＝9.6Hz，1H)，5.93-5.82(m，1H)，5.27-5.20(m，1H)，5.13-5.07(m，1H)，4.33-4.26(m，2H)，3.40-3.28(m，2H)，2.76-2.67(m，2H)，2.47-2.39(m，2H)，2.18-2.08(m，1H)，1.93-1.80(m，4H)，1.61-1.50(m，2H)； ¹³C?NMR(CD ₃OD)δ162.9，140.3，139.0，135.5，131.1，129.2，122.6，121.3，120.4，115.5，114.7，74.2，68.7，55.3，51.0，40.6，30.9，24.9。

[0366] product is dissolved in acetone, adds the oxalic acid (1.1 equivalent) that is dissolved in acetone.Filter the crystal that forms, use washing with acetone, obtain the oxalates (0.140g) of title compound.HPLC-MS (ammonium acetate) [M+H] ⁺=327.3.

Universal method 18 (GP18)

[0367] in the 7mL bottle, add the heterocyclic compound (1 equivalent) be dissolved among the MeCN (4mL), (R, S)-1-bromo-3-chloro-2-methylpropane (1.2 equivalent) and Cs ₂CO ₃(2 equivalent), and under 50 ℃, stir 20h.Add entry to reactant mixture, product extracts with EtOAc.Merge organic layer, filter, concentrate with the PTFF filter.Product is used for the next step without being further purified.

(R, S)-4-(3-chloro-2-methyl-propyl)-6-methyl-4H-benzo [1,4] oxazine-3-ketone (112KK19-a)

[0368] according to GP18 make 6-methyl-4H-benzo of being dissolved among the MeCN (4mL) [1,4] oxazine-3-ketone (and 0.512g, 3.14mmol), (R, S)-1-bromo-3-chloro-2-methylpropane (0.646g, 3.77mmol) and Cs ₂CO ₃(2.036g 6.25mmol) reacts, and obtains the crude product (0.692g) of title compound (112KK19-a).

(R, S)-4-(3-chloro-2-methyl-propyl)-6-fluoro-4H-benzo [1,4] oxazine-3-ketone (112KK19-b)

[0369] according to GP18 make the 6-fluoro-4H-benzo that is dissolved among the MeCN (4mL) [1,4] oxazine-3-ketone (and 0.502g, 3.00mmol), (R, S)-1-bromo-3-chloro-2-methylpropane (0.617g, 3.60mmol) and Cs ₂CO ₃(1.983g 6.09mmol) reacts, and obtains the crude product (0.768g) of title compound (112KK19-b).

(R, S)-4-(3-chloro-2-methyl-propyl)-7-fluoro-4H-benzo [1,4] oxazine-3-ketone (112KK19-c)

[0370] according to GP18 make the 7-fluoro-4H-benzo that is dissolved among the MeCN (4mL) [1,4] oxazine-3-ketone (and 0.498g, 2.98mmol), (R, S)-1-bromo-3-chloro-2-methylpropane (0.613g, 3.58mmol) and Cs ₂CO ₃(1.985g 6.09mmol) reacts, and obtains the crude product (0.694g) of title compound (112KK19-c).

(R, S)-3-(3-chloro-2-methyl-propyl)-3H-benzothiazole-2-ketone (112KK19-d)

[0371] according to GP18 make benzothiazole-2-alcohol of being dissolved among the MeCN (4mL) (0.476g, 3.15mmol), (R, S)-1-bromo-3-chloro-2-methylpropane (0.648g, 3.78mmol) and Cs ₂CO ₃(2.024g 6.21mmol) reacts, and obtains the crude product (0.804g) of title compound (112KK19-d).

Universal method 19 (GP19)

[0372] in the 7mL bottle, add the heterocyclic compound (1 equivalent) be dissolved among the MeCN (3mL), (R, S)-1-bromo-3-chloro-2-methylpropane (1 equivalent) and Cs ₂CO ₃(1.5 equivalent), and under 50 ℃, stir 20h.Add entry to reactant mixture, product extracts with EtOAc.Merge organic layer, use Na ₂SO ₄Drying is filtered, and concentrates.Product is with quick CC (SiO ₂EtOAc/ normal heptane 1: 1) purification.

(R, S)-4-(3-chloro-2-methyl-propyl)-4H-benzo [1.4] oxazine-3-ketone (107LH61-1)

[0373] according to GP19 make the 4H-benzo that is dissolved among the MeCN (3mL) [1.4] oxazine-2-ketone (and 0.447g, 3.0mmol), (R, S)-1-bromo-3-chloro-2-methylpropane (0.514g, 3.0mmol) and Cs ₂CO ₃(1.466g 4.5mmol) reacts also purification, obtains the crude product (0.595g) of title compound (107LH61-1).

(R, S)-4-(3-chloro-2-methyl-propyl)-4H-benzo [1.4] thiazine-3-ketone (107LH61-2)

[0374] according to GP19 make 4H-benzo [1.4] thiazine-3-ketone of being dissolved among the MeCN (3mL) (0.496g, 3.0mmol), (R, S)-1-bromo-3-chloro-2-methylpropane (0.514g, 3.0mmol) and Cs ₂CO ₃(1.466g 4.5mmol) reacts also purification, obtains the crude product (0.593g) of title compound (107LH61-2).

(R, S)-4-(3-chloro-2-methyl-propyl)-6-methoxyl group-4H-benzo [1,4] oxazine-3-ketone (107LH69)

[0375] according to GP19 make 6-methoxyl group-4H-benzo of being dissolved among the MeCN (3mL) [1,4] oxazine-3-ketone (111MF24) (and 0.538g, 3.0mmol), (R, S)-1-bromo-3-chloro-2-methylpropane (0.514g, 3.0mmol) and Cs ₂CO ₃(1.466g 4.5mmol) reacts also purification, obtains the crude product (0.658g) of title compound (107LH69).

(R, S)-1-(3-chloro-2-methyl-propyl)-3,4-dihydro-1H-quinoline-2-one-(107LH63)

[0376] adding is dissolved in 3 of dried DMF (10mL) in reaction flask, and 4-dihydro-1H-quinoline-2-one-(1.00g, 6.8mmol).(0.300g, 7.5mmol), 1h stirs the mixture under room temperature in argon to add NaH 60%.Add then (R, S)-(1.165g 6.8mmol), at room temperature stirs 20h to 1-bromo-3-chloro-2-methylpropane then.Concentrate crude product, with quick CC (SiO ₂EtOAc/ normal heptane 1: 1) purification obtains the crude product (0.753g) of title compound (107LH63).

Universal method 20 (GP20)

[0377] in the 4mL bottle, add the crude product be dissolved in the heterocyclic compound among the DMF, amine, NaI (0.100g, 0.67mmol) and K ₂CO ₃(0.075g 0.54mmol), and stirred 5 days under 100 ℃.Add entry to reactant mixture, product extracts with EtOAc.Crude product with preparation property RP-HPLC purification, obtains title compound then with cation exchange CC purification.

(R, S)-4-[3-(4-butyl piperidine base-1)-2-methyl-propyl]-6-methyl-4H-benzo [1,4] oxazine-3-ketone (112KK20-a1)

[0378] makes (R that is dissolved among the DMF (1.4mL) according to GP20, S)-4-(3-chloro-2-methyl-propyl)-6-methyl-4H-benzo [1, the crude product (0.046g) of 4] oxazine-3-ketone (112KK19-a), 4-butyl piperidine (0.050g, 0.35mmol), NaI (0.100g, 0.67mmol) and K ₂CO ₃(0.075g, 0.54mmol) reaction and purification obtain title compound (112KK20-a1) (0.007g).HPLC-MS (ammonium acetate) [M+H] ⁺=359.32.

(R, S)-4-[2-methyl-3-(propyl group of 4-propoxyl group piperidyl-1-)]-6-methyl-4H-benzo [1.4] oxazine-3- Ketone (112KK20-a2)

[0379] makes (R that is dissolved among the DMF (1.4mL) according to GP20, S)-4-(3-chloro-2-methyl-propyl)-6-methyl-4H-benzo [1, the crude product (0.046g) of 4] oxazine-3-ketone (112KK19-a), 4-propoxyl group piperidines (0.050g, 0.35mmol), NaI (0.100g, 0.67mmol) and K ₂CO ₃(0.075g, 0.54mmol) reaction and purification obtain title compound (112KK20-a2) (0.010g).HPLC-MS (ammonium acetate) [M+H] ⁺=361.29.

(R, S)-4-[3-(4-butylidene piperidyl-1)-2-methyl-propyl]-6-methyl-4H-benzo [1.4] oxazine-3- Ketone (112KK20-a3)

[0380] makes (R that is dissolved among the DMF (1.4mL) according to GP20, S)-4-(3-chloro-2-methyl-propyl)-6-methyl-4H-benzo [1, the crude product (0.046g) of 4] oxazine-3-ketone (112KK19-a), 4-butylidene piperidines (0.053g, 0.38mmol), NaI (0.100g, 0.67mmol) and K ₂CO ₃(0.075g, 0.54mmol) reaction and purification obtain title compound (112KK20-a3) (0.008g).HPLC-MS (ammonium acetate) [M+H] ⁺=357.30.

(R, S)-4-[3-(3-butyl-8-azabicyclo [3.2.1] octyl group-8)-2-methyl-propyl]-6-methyl-4H-benzo [1,4] oxazine-3-ketone (112KK20-a4)

[0381] makes (R that is dissolved among the DMF (1.2mL) according to GP20, S)-4-(3-chloro-2-methyl-propyl)-6-methyl-4H-benzo [1, the crude product (0.023g) of 4] oxazine-3-ketone (112KK19-a), 3-butyl-8-azabicyclo [3.2.1] octane (0.025g, 0.15mmol), NaI (0.100g, 0.67mmol) and K ₂CO ₃(0.075g, 0.54mmol) reaction and purification obtain title compound (112KK20-a4) (0.007g).HPLC-MS (ammonium acetate) [M+H] ⁺=385.32.

(R, S)-4-[2-methyl-3-(propyl group of 3-amyl group-8-azabicyclo [3.2.1] octyl group-8-)]-6-methyl-4H-benzene And [1.4] oxazine-3-ketone (112KK20-a5)

[0382] makes (R that is dissolved among the DMF (1.2mL) according to GP20, S)-4-(3-chloro-2-methyl-propyl)-6-methyl-4H-benzo [1, the crude product (0.023g) of 4] oxazine-3-ketone (112KK19-a), 3-amyl group-8-azabicyclo [3.2.1] octane (0.024g, 0.13mmol), NaI (0.100g, 0.67mmol) and K ₂CO ₃(0.075g, 0.54mmol) reaction and purification obtain title compound (112KK20-a5) (0.002g).HPLC-MS (ammonium acetate) [M+H] ⁺=399.35.

(R, S)-4-[3-(4-butyl piperidine base-1)-2-methyl-propyl]-6-fluoro-4H-benzo [1.4] oxazine-3-ketone (112KK20-b1)

[0383] makes (R that is dissolved among the DMF (1.4mL) according to GP20, S)-4-(3-chloro-2-methyl-propyl)-6-fluoro-4H-benzo [1, the crude product (0.051g) of 4] oxazine-3-ketone (112KK19-b), 4-butyl piperidine (0.050g, 0.35mmol), NaI (0.1 00g, 0.67mmol) and K ₂CO ₃(0.075g, 0.54mmol) reaction and purification obtain title compound (112KK20-b1) (0.011g).HPLC-MS (ammonium acetate) [M+H] ⁺=363.28.

(R, S)-6-fluoro-4-[2-methyl-3-(propyl group of 4-propoxyl group piperidyl-1-)]-4H-benzo [1.4] oxazine-3-ketone (112KK20-b2)

[0384] makes (R that is dissolved among the DMF (1.4mL) according to GP20, S)-4-(3-chloro-2-methyl-propyl)-6-fluoro-4H-benzo [1, the crude product (0.051g) of 4] oxazine-3-ketone (112KK19-b), 4-propoxyl group piperidines (0.050g, 0.35mmol), NaI (0.100g, 0.67mmol) and K ₂CO ₃(0.075g, 0.54mmol) reaction and purification obtain title compound (112KK20-b2) (0.010g).HPLC-MS (ammonium acetate) [M+H] ⁺=365.26.

(R, S)-4-[3-(4-butylidene piperidyl-1)-2-methyl-propyl-6-fluoro-4H-benzo [1,4] oxazine-3-ketone (112KK20-b3)

[0385] makes (R that is dissolved among the DMF (1.4mL) according to GP20, S)-4-(3-chloro-2-methyl-propyl)-6-fluoro-4H-benzo [1,4] oxazine-3-ketone (1 12KK1 9-b) (0.051g), 4-butylidene piperidines (0.053g, 0.38mmol), NaI (0.100g, 0.67mmol) and K ₂CO ₃(0.075g, 0.54mmol) reaction and purification obtain title compound (112KK20-b3) (0.011g).HPLC-MS (ammonium acetate) [M+H] ⁺=361.27.

(R, S)-4-[3-(3-butyl-8-azabicyclo [3.2.1] octyl group-8)-2-methyl-propyl]-6-fluoro-4H-benzo [1.4] oxazine-3-ketone (112KK20-b4)

[0386] makes (R that is dissolved among the DMF (1.2mL) according to GP20, S)-4-(3-chloro-2-methyl-propyl)-6-fluoro-4H-benzo [1, the crude product (0.026g) of 4] oxazine-3-ketone (112KK19-b), 3-butyl-8-azabicyclo [3.2.1] octane (0.025g, 0.15mmol), NaI (0.100g, 0.67mmol) and K ₂CO ₃(0.075g, 0.54mmol) reaction and purification obtain title compound (112KK20-b4) (0.009g).HPLC-MS (ammonium acetate) [M+H] ⁺=389.30.

(R, S)-6-fluoro-4-[2-methyl-3-(propyl group of 3-amyl group-8-azabicyclo [3.2.1] octyl group-8-)]-the 4H-benzo [1,4] oxazine-3-ketone (112KK20-b5)

[0387] makes (R that is dissolved among the DMF (1.2mL) according to GP20, S)-4-(3-chloro-2-methyl-propyl)-6-fluoro-4H-benzo [1, the crude product (0.026g) of 4] oxazine-3-ketone (112KK19-b), 3-amyl group-8-azabicyclo [3.2.1] octane (0.024g, 0.13mmol), NaI (0.100g, 0.67mmol) and K ₂CO ₃(0.075g, 0.54mmol) reaction and purification obtain title compound (112KK20-b5) (0.009g).HPLC-MS (ammonium acetate) [M+H] ⁺=403.31.

(R, S)-4-[3-(4-butyl piperidine base-1)-2-methyl-propyl]-7-fluoro-4H-benzo [1,4] oxazine-3-ketone (112KK20-c1)

[0388] makes (R that is dissolved among the DMF (1.4mL) according to GP20, S)-4-(3-chloro-2-methyl-propyl)-7-fluoro-4H-benzo [1, the crude product (0.046g) of 4] oxazine-3-ketone (112KK19-c), 4-butyl piperidine (0.050g, 0.35mmol), NaI (0.100g, 0.67mmol) and K ₂CO ₃(0.075g, 0.54mmol) reaction and purification obtain title compound (112KK20-c1) (0.002g).HPLC-MS (ammonium acetate) [M+H] ⁺=363.29.

(R, S)-7-fluoro-4-[2-methyl-3-(propyl group of 4-propoxyl group piperidyl-1-)]-4H-benzo [1,4] oxazine-3-ketone (112KK20-c2)

[0389] makes (R that is dissolved among the DMF (1.4mL) according to GP20, S)-4-(3-chloro-2-methyl-propyl)-7-fluoro-4H-benzo [1, the crude product (0.046g) of 4] oxazine-3-ketone (112KK19-c), 4-propoxyl group piperidines (0.050g, 0.35mmol), NaI (0.100g, 0.67mmol) and K ₂CO ₃(0.075g, 0.54mmol) reaction and purification obtain title compound (112KK20-c2) (0.002g).HPLC-MS (ammonium acetate) [M+H] ⁺=365.28.

(R, S)-4-[3-(4-butylidene piperidyl-1)-2-methyl-propyl]-7-fluoro-4H-benzo [1,4] oxazine-3-ketone (112KK20-c3)

[0390] makes (R that is dissolved among the DMF (1.4mL) according to GP20, S)-4-(3-chloro-2-methyl-propyl)-7-fluoro-4H-benzo [1, the crude product (0.046g) of 4] oxazine-3-ketone (112KK19-c), 4-butylidene piperidines (0.053g, 0.38mmol), NaI (0.100g, 0.67mmol) and K ₂CO ₃(0.075g, 0.54mmol) reaction and purification obtain title compound (112KK20-c3) (0.008g).HPLC-MS (ammonium acetate) [M+H] ⁺=361.29.

(R, S)-4-[3-(3-butyl-8-azabicyclo [3.2.1] octyl group-8-]-2-methyl-propyl-7-fluoro-4H-benzo [1,4] oxazine-3-ketone (112KK20-c4)

[0391] makes (R that is dissolved among the DMF (1.2mL) according to GP20, S)-4-(3-chloro-2-methyl-propyl)-7-fluoro-4H-benzo [1, the crude product (0.023g) of 4] oxazine-3-ketone (112KK19-c), 3-butyl-8-azabicyclo [3.2.1] octane (0.025g, 0.15mmol), NaI (0.100g, 0.67mmol) and K ₂CO ₃(0.075g, 0.54mmol) reaction and purification obtain title compound (112KK20-c4) (0.004g).HPLC-MS (ammonium acetate) [M+H] ⁺=389.31.

(R, S)-7-fluoro-4-[2-methyl-3-(propyl group of 3-amyl group-8-azabicyclo [3.2.1] octyl group-8-)]-the 4H-benzo [1,4] oxazine-3-ketone (112KK20-c5)

[0392] makes (R that is dissolved among the DMF (1.2mL) according to GP20, S)-4-(3-chloro-2-methyl-propyl)-7-fluoro-4H-benzo [1, the crude product (0.023g) of 4] oxazine-3-ketone (112KK19-c), 3-amyl group-8-azabicyclo [3.2.1] octane (0.024g, 0.13mmol), NaI (0.100g, 0.67mmol) and K ₂CO ₃(0.075g, 0.54mmol) reaction and purification obtain title compound (112KK20-c5) (0.002g).HPLC-MS (ammonium acetate) [M+H] ⁺=403.32.

(R, S)-3-[3-(4-butyl piperidine base-1)-2-methyl-propyl-3H-benzothiazole-2-ketone (112KK20-d1)

[0393] makes (R that is dissolved among the DMF (1.4mL) according to GP20, S)-3-(3-chloro-2-the methyl-propyl)-crude product (0.054g) of 3H-benzothiazole-2-ketone (112KK19-d), 4-butyl piperidine (0.050g, 0.35mmol), NaI (0.100g, 0.67mmol) and K ₂CO ₃(0.075g, 0.54mmol) reaction and purification obtain title compound (112KK20-d1) (0.012g).HPLC-MS (ammonium acetate) [M+H] ⁺=347.28.

(R, S)-4-[2-methyl-3-(propyl group of 4-propoxyl group piperidyl-1-)]-3H-benzothiazole-2-ketone (112KK20-d2)

[0394] makes (R that is dissolved among the DMF (1.4mL) according to GP20, S)-3-(3-chloro-2-the methyl-propyl)-crude product (0.054g) of 3H-benzothiazole-2-ketone (112KK19-d), 4-propoxyl group piperidines (0.050g, 0.35mmol), NaI (0.100g, 0.67mmol) and K ₂CO ₃(0.075g, 0.54mmol) reaction and purification obtain title compound (112KK20-d2) (0.011g).HPLC-MS (ammonium acetate) [M+H] ⁺=349.25.

(R, S)-4-[3-(4-butylidene piperidyl-1)-2-methyl-propyl]-3H-benzothiazole-2-ketone (112KK20-d3)

[0395] makes (R that is dissolved among the DMF (1.4mL) according to GP20, S)-3-(3-chloro-2-the methyl-propyl)-crude product (0.054g) of 3-benzothiazole-2-ketone (112KK19-d), 4-butylidene piperidines (0.053g, 0.38mmol), NaI (0.100g, 0.67mmol) and K ₂CO ₃(0.075g, 0.54mmol) reaction and purification obtain title compound (112KK20-d3) (0.011g).HPLC-MS (ammonium acetate) [M+H] ⁺=345.27.

(R, S)-3-[-(3-butyl-8-azabicyclo [3.2.1] octyl group-8)-2-methyl-propyl]-3H-benzothiazole-2- Ketone (112KK20-d4)

[0396] makes (R that is dissolved among the DMF (1.2mL) according to GP20, S)-crude product (0.027g) of 3-(3-chloro-2-methyl-propyl)-3H-benzothiazole-2-ketone (112KK19-d), 3-butyl-8-azabicyclo [3.2.1] octane (0.025g, 0.15mmol), NaI (0.100g, 0.67mmol) and K ₂CO ₃(0.075g, 0.54mmol) reaction and purification obtain title compound (112KK20-d4) (0.011g).HPLC-MS (ammonium acetate) [M+H] ⁺=373.30.

(R, S)-3-[2-methyl-3-(propyl group of 3-amyl group-8-azabicyclo [3.2.1] octyl group-8-)]-the 3H-benzothiazole -2-ketone (112KK20-d5)

[0397] makes (R that is dissolved among the DMF (1.2mL) according to GP20, S)-crude product (0.027g) of 3-(3-chloro-2-methyl-propyl)-3H-benzothiazole-2-ketone (112KK19-d), 3-amyl group-8-azabicyclo [3.2.1] octane (0.024g, 0.13mmol), NaI (0.100g, 0.67mmol) and K ₂CO ₃(0.075g, 0.54mmol) reaction and purification obtain title compound (112KK20-d5) (0.011g).HPLC-MS (ammonium acetate) [M+H] ⁺=387.30.

(R, S)-4-[3-(4-butyl piperidine base-1)-2-methyl-propyl]-4H-benzo [1,4] oxazine-3-ketone (107LH74-a1)

[0398] makes (R that is dissolved among the DMF (1mL) according to GP20, S)-4-(3-chloro-2-methyl-propyl)-4H-benzo [1, the crude product (0.149g) of 4] oxazine-3-ketone (107LH61-1), 4-butyl piperidine (0.042g, 0.30mmol), NaI (0.100g, 0.67mmol) and K ₂CO ₃(0.075g, 0.54mmol) reaction and purification obtain title compound (107LH74-a1) (0.092g).HPLC-MS (ammonium acetate) [M+H] ⁺=345.30.

(R, S)-4-[2-methyl-3-(propyl group of 4-propoxyl group piperidyl-1-)]-4H-benzo [1,4] oxazine-3-ketone (107LH74-a2)

[0399] makes (R that is dissolved among the DMF (1mL) according to GP20, S)-4-(3-chloro-2-methyl-propyl)-4H-benzo [1, the crude product (0.149g) of 4] oxazine-3-ketone (107LH61-1), 4-propoxyl group piperidines (0.043g, 0.30mmol), NaI (0.100g, 0.67mmol) and K ₂CO ₃(0.075g, 0.54mmol) reaction and purification obtain title compound (107LH74-a2) (0.077g).HPLC-MS (ammonium acetate) [M+H] ⁺=347.30.

(R, S)-4-[3-(4-butylidene piperidyl-1)-2-methyl-propyl]-4H-benzo [1,4] oxazine-3-ketone (107LH74-a3)

[0400] makes (R that is dissolved among the DMF (1mL) according to GP20, S)-4-(3-chloro-2-methyl-propyl)-4H-benzo [1, the crude product (0.149g) of 4] oxazine-3-ketone (107LH61-1), 4-butylidene piperidines (0.042g, 0.30mmol), NaI (0.100g, 0.67mmol) and K ₂CO ₃(0.075g, 0.54mmol) reaction and purification obtain title compound (107LH74-a3) (0.083g).HPLC-MS (ammonium acetate) [M+H] ⁺=343.30.

(R, S)-4-[3-(3-butyl-8-azabicyclo [3.2.1] octyl group-8)-2-methyl-propyl]-4H-benzo [1,4] Evil Piperazine-3-ketone (107LH74-a4)

[0401] makes (R that is dissolved among the DMF (1mL) according to GP20, S)-4-(3-chloro-2-methyl-propyl)-4H-benzo [1, the crude product (0.074g) of 4] oxazine-3-ketone (107LH61-1), 3-butyl-8-azabicyclo [3.2.1] octane (0.025g, 0.15mmol), NaI (0.100g, 0.67mmol) and K ₂CO ₃(0.075g, 0.54mmol) reaction and purification obtain title compound (107LH74-a4) (0.046g).HPLC-MS (ammonium acetate) [M+H] ⁺=371.33.

(R, S)-4-[2-methyl-3-(propyl group of 3-amyl group-8-azabicyclo [3.2.1] octyl group-8-)]-4H-benzo [1,4] Evil Piperazine-3-ketone (107LH74-a5)

[0402] makes (R that is dissolved among the DMF (1mL) according to GP20, S)-4-(3-chloro-2-methyl-propyl)-4H-benzo [1, the crude product (0.074g) of 4] oxazine-3-ketone (107LH61-1), 3-amyl group-8-azabicyclo [3.2.1] octane (0.027g, 0.15mmol), NaI (0.100g, 0.67mmol) and K ₂CO ₃(0.075g, 0.54mmol) reaction and purification obtain title compound (107LH74-a5) (0.053g).HPLC-MS (ammonium acetate) [M+H] ⁺=385.34.

(R, S)-4-[3-(4-butyl piperidine base-1)-2-methyl-propyl]-4H-benzo [1,4] thiazine-3-ketone (107LH74-b1)

[0403] makes (R that is dissolved among the DMF (1mL) according to GP20, S)-4-(3-chloro-2-methyl-propyl)-4H-benzo [1,4] crude product (0.148g) of thiazine-3-ketone (107LH61-2), 4-butyl piperidine (0.042g, 0.30mmol), NaI (0.1 00g, 0.67mmol) and K ₂CO ₃(0.075g, 0.54mmol) reaction and purification obtain title compound (107LH74-b1) (0.083g).HPLC-MS (ammonium acetate) [M+H] ⁺=361.29.

(R, S)-1-[2-methyl-3-(propyl group of 4-propoxyl group piperidyl-1-)]-4H-benzo [1,4] thiazine-3-ketone (107LH74-b2)

[0404] makes (R that is dissolved among the DMF (1mL) according to GP20, S)-1-(3-chloro-2-methyl-propyl)-4H-benzo [1,4] crude product (0.148g) of thiazine-3-ketone (107LH61-2), 4-propoxyl group piperidines (0.043g, 0.30mmol), NaI (0.100g, 0.67mmol) and K ₂CO ₃(0.075g, 0.54mmol) reaction and purification obtain title compound (107LH74-b2) (0.071g).HPLC-MS (ammonium acetate) [M+H] ⁺=363.27.

(R, S)-4-[3-(4-butylidene piperidyl-1)-2-methyl-propyl]-4H-benzo [1,4] thiazine-3-ketone (107LH74-b3)

[0405] makes (R that is dissolved among the DMF (1mL) according to GP20, S)-4-(3-chloro-2-methyl-propyl)-4H-benzo [1,4] crude product (0.148g) of thiazine-3-ketone (107LH61-2), 4-butylidene piperidines (0.042g, 0.30mmol), NaI (0.100g, 0.67mmol) and K ₂CO ₃(0.075g, 0.54mmol) reaction and purification obtain title compound (107LH74-b3) (0.064g).HPLC-MS (ammonium acetate) [M+H] ⁺=359.27.

(R, S)-4-[3-(3-butyl-8-azabicyclo [3.2.1] octyl group-8)-2-methyl-propyl]-4H-benzo [1,4] thiophene Piperazine-3-ketone (107LH74-b4)

[0406] makes (R that is dissolved among the DMF (1mL) according to GP20, S)-4-(3-chloro-2-methyl-propyl)-4H-benzo [1,4] crude product (0.074g) of thiazine-3-ketone (107LH61-2), 3-butyl-8-azabicyclo [3.2.1] octane (0.025g, 0.15mmol), NaI (0.100g, 0.67mmol) and K ₂CO ₃(0.075g, 0.54mmol) reaction and purification obtain title compound (107LH74-b4) (0.040g).HPLC-MS (ammonium acetate) [M+H] ⁺=387.30.

(R, S)-4-[2-methyl-3-(propyl group of 3-amyl group-8-azabicyclo [3.2.1] octyl group-8-)]-4H-benzo [1,4] thiophene Piperazine-3-ketone (107LH74-b5)

[0407] makes the crude product (R that is dissolved among the DMF (1mL) according to GP20, S)-4-(3-chloro-2-methyl-propyl)-4H-benzo [1,4] thiazine-3-ketone (107LH61-2) (0.074g), 3-amyl group-8-azabicyclo [3.2.1] octane (0.027g, 0.15mmol), NaI (0.100g, 0.67mmol) and K ₂CO ₃(0.075g, 0.54mmol) in DMF (1mL) reaction and purification obtain title compound (107LH74-b5) (0.040g).HPLC-MS (ammonium acetate) [M+H] ⁺=401.30.

(R, S)-1-[3-(4-butyl piperidine base-1)-2-methyl-propyl]-3,4-dihydro-1H-quinoline-2-one- (107LH74-c1)

[0408] makes (R that is dissolved among the DMF (1mL) according to GP20, S)-1-(3-chloro-2-methyl-propyl)-3, the crude product (0.188g) of 4-dihydro-1H-quinoline-2-one-(107LH63), 4-butyl piperidine (0.042g, 0.30mmol), NaI (0.100g, 0.67mmol) and K ₂CO ₃(0.075g, 0.54mmol) reaction and purification obtain title compound (107LH74-c1) (0.047g).HPLC-MS (ammonium acetate) [M+H] ⁺=343.32.

(R, S)-1-[2-methyl-3-(propyl group of 4-propoxyl group piperidyl-1-)]-3,4-dihydro-1H-quinoline-2-one- (107LH74-c2)

[0409] makes (R that is dissolved among the DMF (1mL) according to GP20, S)-1-(3-chloro-2-methyl-propyl)-3, the crude product (0.188g) of 4-dihydro-1H-quinoline-2-one-(107LH63), 4-propoxyl group piperidines (0.043g, 0.30mmol), NaI (0.100g, 0.67mmol) and K ₂CO ₃(0.075g, 0.54mmol) reaction and purification obtain title compound (107LH74-c2) (0.040g).HPLC-MS (ammonium acetate) [M+H] ⁺=345.32.

(R, S)-1-[3-(4-butylidene piperidyl-1)-2-methyl-propyl-3,4-dihydro-1H-quinoline-2-one- (107LH74-c3)

[0410] makes (R that is dissolved among the DMF (1mL) according to GP20, S)-1-(3-chloro-2-methyl-propyl)-3, the crude product (0.188g) of 4-dihydro-1H-quinoline-2-one-(107LH63), 4-butylidene piperidines (0.042g, 0.30mmol), NaI (0.100g, 0.67mmol) and K ₂CO ₃(0.075g, 0.54mmol) reaction and purification obtain title compound (107LH74-c3) (0.038g).HPLC-MS (ammonium acetate) [M+H] ⁺=341.31.

(R, S)-1-[3-(3-butyl-8-azabicyclo [3.2.1] octyl group-8)-2-methyl-propyl]-3,4-dihydro-1H-quinoline Quinoline-2-ketone (107LH74-c4)

[0411] makes (R that is dissolved among the DMF (1mL) according to GP20, S)-1-(3-chloro-2-methyl-propyl)-3, the crude product (0.094g) of 4-dihydro-1H-quinoline-2-one-(107LH63), 3-butyl-8-azabicyclo [3.2.1] octane (0.025g, 0.15mmol), NaI (0.100g, 0.67mmol) and K ₂CO ₃(0.075g, 0.54mmol) reaction and purification obtain title compound (107LH74-c4) (0.025g).HPLC-MS (ammonium acetate) [M+H] ⁺=369.33.

(R, S)-1-[2-methyl-3-(propyl group of 3-amyl group-8-azabicyclo [3.2.1] octyl group-8-)]-3,4-dihydro-1H-quinoline Quinoline-2-ketone (107LH74-c5)

[0412] makes (R that is dissolved among the DMF (1mL) according to GP20, S)-1-(3-chloro-2-methyl-propyl)-3, the crude product (0.094g) of 4-dihydro-1H-quinoline-2-one-(107LH63), 3-amyl group-8-azabicyclo [3.2.1] octane (0.027g, 0.15mmol), NaI (0.100g, 0.67mmol) and K ₂CO ₃(0.075g, 0.54mmol) reaction and purification obtain title compound (107LH74-c5) (0.023g).HPLC-MS (ammonium acetate) [M+H] ⁺=383.34.

(R, S)-4-[3-(4-butyl piperidine base-1)-2-methyl-propyl]-6-methoxyl group-4H-benzo [1,4] oxazine-3- Ketone (107LH74-d1)

[0413] makes (R that is dissolved among the DMF (1mL) according to GP20, S)-4-(3-chloro-2-methyl-propyl)-6-methoxyl group-4H-benzo [1, the crude product (0.165g) of 4] oxazine-3-ketone (107LH69), 4-butyl piperidine (0.042g, 0.30mmol), NaI (0.100g, 0.67mmol) and K ₂CO ₃(0.075g, 0.54mmol) reaction and purification obtain title compound (107LH74-d1) (0.094g).HPLC-MS (ammonium acetate) [M+H] ⁺=375.31.

(R, S)-4-[2-methyl-3-(4-propoxyl group piperidyl-1)-6-methoxyl group]-4H-benzo [1,4] oxazine-3-ketone (107LH74-d2)

[0414] makes (R that is dissolved among the DMF (1mL) according to GP20, S)-4-(3-chloro-2-methyl-propyl)-6-methoxyl group-4H-benzo [1, the crude product (0.165g) of 4] oxazine-3-ketone (107LH69), 4-propoxyl group piperidines (0.043g, 0.30mmol), NaI (0.100g, 0.67mmol) and K ₂CO ₃(0.075g, 0.54mmol) reaction and purification obtain title compound (107LH74-d2) (0.086g).HPLC-MS (ammonium acetate) [M+H] ⁺=377.29.

(R, S)-4-[3-(4-butylidene piperidyl-1)-2-methyl-propyl]-6-methoxyl group-4H-benzo [1,4] oxazine -3-ketone (107LH74-d3)

[0415] makes (R that is dissolved among the DMF (1mL) according to GP20, S) 4-(3-chloro-2-methyl-propyl)-6-methoxyl group-4H-benzo [1, the crude product (0.165g) of 4] oxazine-3-ketone (107LH69), 4-butylidene piperidines (0.042g, 0.30mmol), NaI (0.100g, 0.67mmol) and K ₂CO ₃(0.075g, 0.54mmol) reaction and purification obtain title compound (107LH74-d3) (0.086g).HPLC-MS (ammonium acetate) [M+H] ⁺=373.29.

(R, S)-4-[3-(3-butyl-8-azabicyclo [3.2.1] octyl group-8)-2-methyl-propyl]-6-methoxyl group-4H-benzene And [1,4] oxazine-3-ketone (107LH74-d4)

[0416] makes (R that is dissolved among the DMF (1mL) according to GP20, S)-4-(3-chloro-2-methyl-propyl)-6-methoxyl group-4H-benzo [1, the crude product (0.082g) of 4] oxazine-3-ketone (107LH69), 3-butyl-8-azabicyclo [3.2.1] octane (0.025g, 0.15mmol), NaI (0.100g, 0.67mmol) and K ₂CO ₃(0.075g, 0.54mmol) reaction and purification obtain title compound (107LH74-d4) (0.044g).HPLC-MS (ammonium acetate) [M+H] ⁺=401.32.

(R, S)-1-[2-methyl-3-(propyl group of 3-amyl group-8-azabicyclo [3.2.1] octyl group-8-)]-6-methoxyl group-4H- Benzo [1,4] oxazine-3-ketone (107LH74-d5)

[0417] makes (R that is dissolved among the DMF (1mL) according to GP20, S)-4-(3-chloro-2-methyl-propyl)-6-methoxyl group-4H-benzo [1, the crude product (0.082g) of 4] oxazine-3-ketone (107LH69), 3-amyl group-8-azabicyclo [3.2.1] octane (0.027g, 0.15mmol), NaI (0.100g, 0.67mmol) and K ₂CO ₃(0.075g, 0.54mmol) reaction and purification obtain title compound (107LH74-d5) (0.051g).HPLC-MS (ammonium acetate) [M+H] ⁺=415.34.

1-[3-(4-butyl-piperidyl-1)-propyl group]-1,2,3,4-tetrahydrochysene-quinoline (55-LH-12-2)

[0418] (1.5M, 7.3mL 11mmol) dropwise are added to 1,2,3, and (1.256mL is in oxolane 10mmol) (10mL) solution for 4-tetrahydrochysene-quinoline with the hexane solution of n-BuLi under-78 ℃ in argon.Stirred reaction mixture 1/2h, add then 1-chloro-3-iodopropane (1.0mL, 9.5mmol).At-78 ℃ of following stirred reaction mixture 1/2h, restir 16h at room temperature then.Evaporate oxolane, will be dissolved in the acetonitrile (10mL).Add KI (1.83g, 11mmol), K ₂CO ₃(2.76g, 20mmol) and the 4-butyl piperidine (1.66mL, 10mmol).Slurry stirs 48h down at 50 ℃, adds entry (10mL) then, and (2 * 20mL) extract product with ethyl acetate.Dry (Na ₂SO ₄) organic layer, vacuum concentration.(eluent: ethyl acetate) purification obtains title compound (1.11g, 35%) to product with column chromatography.With oxalic acid (1.1 equivalent) the preparation oxalates that is dissolved in the acetone.HPLC-MS：M+1 ⁺＝315.1(MS(％)＝95)。 ¹H NMR (400MHz, CHCl ₃): δ=0.89 (3H, t), 1.18-1.34 (9H, m), 1.64-1.70 (2H, m), 1.79 (2H, quinoline), 1.85-1.98 (4H, m), 2.36 (2H, t), 2.74 (2H, t), (2.92 2H, broad d), and 3.24-3.31 (4H, m), 6.54 (1H, ddd), 6.60 (1H, dd), 6.93 (1H, dd), 7.03 (1H, ddd). ¹³C?NMR(CDCl ₃)：δ14.3，22.5，23.1，24.2，28.4，29.3，32.7，36.0，36.5，49.6，49.8，54.4，56.7，110.9，115.5，122.5，127.3，129.3，145.6。

1-[3-(4-butyl-piperidyl-1)-propyl group]-the 2-methyl isophthalic acid, 2,3,4-tetrahydrochysene-quinoline (55-LH-28-8)

[0419] according to synthetic 1-[3-(4-butyl-piperidyl-1)-propyl group]-1,2,3, the method for 4-tetrahydrochysene-quinoline, with the 2-methyl isophthalic acid, 2,3, (346mg 2.35mmol) changes into title product to the 4-tetrahydroquinoline.Productive rate: 88.6mg, 11%.HPLC-MS：M+1 ⁺＝329.5(UV/MS(％)＝100/99)。 ¹H?NMR(400MHz，CHCl ₃)：δ＝0.89(3H，t)，1.11(3H，d)，1.16-1.34(9H，m)，1.67(2H，broadd)，1.65-2.03(8H，m)，2.39(2H，t)，2.57-2.66(1H，m)，2.74-2.85(1H，m)，2.93(2H，broad?d)，3.12-3.21(1H，m)，3.33-3.42(1H，m)，3.44-3.52(1H，m)，6.45(1H，t)，6.54(1H，d)，6.87(1H，d)，6.97(1H，t)。 ¹³C?NMR(CD ₃OD)：δ13.2，17.8，22.8，23.7，24.4，28.0，28.9，31.9，35.7，36.2，52.7，53.9，54.0，56.4，110.8，115.1，121.9，126.7，128.7，144.2。

1-[3-(4-butyl-piperidyl-1)-propyl group-6-methyl isophthalic acid, 2,3,4-tetrahydrochysene-quinoline (55-LH-44A)

[0420] according to synthetic 1-[3-(4-butyl-piperidyl-1)-propyl group]-1,2,3, the method for 4-tetrahydrochysene-quinoline, with the 6-methyl isophthalic acid, 2,3, (346mg 2.35mmol) changes into title product to the 4-tetrahydroquinoline.Productive rate: 137mg, 18%.HPLC-MS：M+1 ⁺＝329.5(UV/MS(％)＝98/99)。 ¹H NMR (400MHz, CDCl ₃): δ=0.89 (3H, t), 1.14-1.34 (9H, m), 1.68 (2H, broad d), 1.76 (2H, quinoline), 1.85-1.99 (4H, m), 2.14 (3H, s), 2.34-2.39 (2H, m), 2.66 (2H, t), 2.92 (2H, broad d), 3.18-3.26 (4H, m), 6.49 (1H, d), (6.58 1H, broad s), 6.76 (1H, broadd). ¹³C?NMR(CD ₃OD)：δ13.2，19.2，22.5，22.8，23.2，28.0，28.9，31.9，35.7，36.2，49.4，49.6，53.9，56.5，111.3，122.7，124.7，127.2，129.6，143.2。

1-[3-(4-butyl-piperidyl-1)-propyl group]-the 8-methyl isophthalic acid, 2,3,4-tetrahydrochysene-quinoline (77-LH-1)

[0421] under 60 ℃, shake the 8-methyl isophthalic acid that is dissolved in the acetonitrile (2mL), 2,3, the 4-tetrahydroquinoline (125mg, 0.85mmol), 1-chloro-3-iodopropane (82 μ l, 0.77mmol) and Cs ₂CO ₃(415mg, 1.27mmol) 7 days.Add KI (140mg, 0.85mmol), K ₂CO ₃(117mg, 0.85mmol) (113 μ l 0.68mmol), shook reactant mixture 2 days under 60 ℃ with the 4-butyl piperidine.Add entry (5mL), (2 * 10mL) extract product with ethyl acetate.Dry (Na ₂SO ₄) organic layer, vacuum concentration.(eluent: the ethyl acetate that contains 20% methanol) purification obtains title compound to the product column chromatography.Productive rate: 45.6mg (20.4%).HPLC-MS：M+1 ⁺＝329.5(UV/MS(％)＝99/97)。 ¹HNMR(400MHz，CDCl ₃)：δ＝0.89(3H，t)，1.18-1.34(9H，m)，1.70(2H，broad?d)，1.75-1.92(4H，m)，1.99(2H，broad?t)，2.22(3H，s)，2.38(2H，dd)，2.70-2.81(4H，m)，2.96(2H，broad?d)，3.04-3.10(2H，m)，6.76(1H，t)，6.80(1H，broad?d)，6.91(1H，broad?d)。 ¹³C?NMR(CD ₃OD)：δ13.2，17.2，18.0，18.1，22.8，25.7，27.7，28.9，31.9，35.7，36.2，52.7，53.9，56.3，121.5，127.1，128.7，128.9，131.0，148.0。

1-[3-(4-butyl-piperidyl-1)-propyl group]-7-fluoro-2-methyl isophthalic acid, 2,3,4-tetrahydrochysene-quinoline (77-LH-2)

[0422] according to synthetic 1-[3-(4-butyl-piperidyl-1)-propyl group]-the 8-methyl isophthalic acid, 2,3, the method for 4-tetrahydrochysene-quinoline, with 7-fluoro-2-methyl isophthalic acid, 2,3, (165mg 1.0mmol) changes into title product to 4-tetrahydrochysene-quinoline.Productive rate: 43.2mg, 16%.HPLC-MS：M+1 ⁺＝347.5(UV/MS(％)＝95/92)。 ¹H?NMR(400MHz，CDCl ₃)：δ＝0.89(3H，t)，1.10(3H，d)，1.18-1.36(9H，m)，1.66-1.91(6H，m)，2.00-2.10(2H，m)，2.44(2H，t)，2.62(1H，dt)，2.74-2.85(1H，m)，2.99(2H，broad?d)，3.16(1H，q)，3.30-3.40(1H，m)，3.41-3.49(1H，m)，6.63-6.74(1H，m)，6.63-6.74(2H，m)。 ¹³C?NMR(CD ₃OD)：δ13.2，17.6，22.7，23.7，23.8，24.3，29.9，28.9，31.7，35.5，36.1，52.6，53.8，56.2，112.7(d)，114.8(d)，123.7，140.8，153.5，155.8。

1-[3-(4-butyl-piperidyl-1)-propyl group]-the 7-Trifluoromethyl-1,2,3,4-tetrahydrochysene-quinoline (55-LH-54)

[0423] according to synthetic 1-[3-(4-butyl-piperidyl-1)-propyl group]-1,2,3, the method for 4-tetrahydrochysene-quinoline, with the 7-Trifluoromethyl-1,2,3, (0.50g 2.5mmol) changes into title product to 4-tetrahydrochysene-quinoline.Productive rate: 1.71mg, 18%.HPLC-MS：M+1 ⁺＝347.5(UV/MS(％)＝99/91)。 ¹HNMR (400MHz, CDCl ₃): δ=0.89 (3H, t), 1.14-1.36 (9H, m), 1.68 (2H, broad d), 1.79 (2H, quinoline), 1.86-2.03 (4H, m), 2.38 (2H, dd), 2.75 (2H, dd), 2.94 (2H, broad d), 3.32 (4H, m), 6.71 (1H, d), 6.75 (1H, s), 6.99 (1H, d).

1-[3-(4-butyl-piperidyl-1)-propyl group]-3,4-dihydro-1H-quinoline-2-one-(77-LH-28-1)

[0424] (712mg) be added to 3 at 0 ℃ of NaH (55-60%) that will suspend down in mineral oil, (2.0g 13.6mmol) is dissolved in N to 4-dihydro-1H-quinoline-2-one-, in the solution that dinethylformamide (50mL) is become.At 0 ℃ of following stirred reaction mixture 1h, add then 1-bromo-3-chloropropane (1.34mL, 13.6mmol).Slurry is restir 16h at room temperature, adds entry (50mL) then, and (2 * 50mL) extract product with ether.Dry (Na ₂SO ₄) organic layer, vacuum concentration.The product purification by flash chromatography (eluent: dichloromethane), obtain the 1-[3-chloropropyl]-3,4-dihydro-1H-quinoline-2-one-(2.41g, 10.8mmol).With KI (2.5g, 15mmol), K ₂CO ₃(2.1g, 15mmol) and the 4-butyl piperidine (1.8mL 15mmol) is added to the 1-[3-chloropropyl]-3, (2.41g 10.8mmol) is dissolved in the solution that acetonitrile (50mL) become 4-dihydro-1H-quinoline-2-one-.Reactant mixture stirs 16h down at 60 ℃.The vacuum evaporation acetonitrile adds entry (50mL), and (2 * 50mL) extract product with ethyl acetate.Dry (Na ₂SO ₄) organic layer, filter vacuum concentration.With purification by flash chromatography (eluent: ethyl acetate), obtain product.Productive rate: 2.06g, 58%.With oxalic acid (1.1 equivalent) the preparation oxalates that is dissolved in the acetone.HPLC-MS：M+1 ⁺＝329.5(UV/MS(％)＝100/100)。 ¹H NMR (400MHz, CD ₃OD): δ=0.89 (3H, t), 1.12-1.36 (9H, m), 1.67 (2H, broad d), 1.83 (2H, quinoline), 1.97 (2H, broad t), 2.41 (2H, t), 2.59 (2H, t), 2.84-2.96 (4H, m), 3.99 (2H, t), (7.02 1H, broad t), 7.16 (1H, broad d), (7.20 1H, broad d), 7.25 (1H, broad t). ¹³C?NMR(CD ₃OD)：δ13.2，22.8，24.3，25.0，28.9，31.6，31.9(2C)，35.6，36.2，40.1，53.8(2C)，55.9，115.2，123.2，127.0，127.4，127.9，139.1，171.5。

1-[3-(4-butyl-piperidyl-1)-propyl group]-6-methoxyl group-3,4-dihydro-1H-quinoline-2-one- (77-LH-22A)

[0425] under 60 ℃, shake the 6-methoxyl group-3 that is dissolved in the acetonitrile (2mL), 4-dihydro-1H-quinoline-2-one-(108mg, 0.61mmol), 1-chloro-3-iodopropane (64 μ l, 0.6mmol) and Cs ₂CO ₃(reaction is chilled to room temperature then for 290mg, 0.9mmol) 14h.Add entry (5mL), (2 * 10mL) extract product with ethyl acetate.Dry (Na ₂SO ₄) organic layer, filter vacuum concentration.Slurry is dissolved in the acetonitrile (4mL).Add KI (83mg, 3.6mmol), K ₂CO ₃(100mg, 0.6mmol) (83 μ l, 0.5mmol), reactant mixture shakes 16h under 60 ℃ with the 4-butyl piperidine.Add entry (5mL), (2 * 10mL) extract product with ethyl acetate.Dry (Na ₂SO ₄) organic layer, vacuum concentration.Product is with column chromatography purification (eluent: the ethyl acetate that contains 20% methanol), obtain title compound.Productive rate: 24.8mg, 11.3%.HPLC-MS：M+1 ⁺＝359.5(UV/MS(％)＝90/78)。 ¹H NMR (400MHz, CHCl ₃): δ=0.89 (3H, t), 1.12-1.34 (9H, m), 1.67 (2H, broad d), 1.85 (2H, quinoline), 1.93 (2H, broad t), 2.39 (2H, t), 2.59 (2H, dd), 2.83 (2H, t), 2.90 (2H, broad d), 3.76 (3H, s), 3.94 (2H, t), 6.70 (1H, d), 6.74 (1H, dd), 7.01 (1H, d). ¹³CNMR(CDCl ₃)：δ14.3，23.0，25.0，26.1，29.2，32.1，32.5(2C)，35.9，36.4，40.8，54.3(2C)，55.8，56.3，112.2，114.2，116.2，128.3，133.4，155.4，169.9。

4-[3-(4-butyl-piperidyl-1)-propyl group]-6-methyl-4H-benzo [1,4] oxazine-3-ketone (64-LHY-89-6)

[0426] under 50 ℃, shake 6-methyl-4H-benzo of being dissolved in the acetonitrile (2mL) [1,4] oxazine-3-ketone (and 82mg, 0.5mmol), 1-chloro-3-iodopropane (50 μ l, 0.5mmol) and Cs ₂CO ₃(163mg, 0.5mmol) 24h, vacuum concentration reactant mixture then.Purified product on Isco CombiFlash Sq 16 * (4g silica column, usefulness contains the heptane eluting of 0-20% ethyl acetate) (the 4-[3-chloropropyl]-6-methyl-4H-benzo [1,4]-oxazines-3-ketone), be dissolved in then in the acetonitrile (2mL).Add K ₂CO ₃(85mg, 0.5mmol) and the 4-butyl piperidine (80 μ l, 0.5mmol).Reactant mixture shakes 16h at 60 ℃, is chilled to room temperature then.Adding dichloromethane (2mL) and PS-isocyanates (1.47mmol/g that packs into, 100mg).5h after-filtration mixture is with the organic layer Varian SCX ion exchange column of packing into.(2 * 5mL) washing pillars elute product with the methanol (6mL) that contains 10% ammonium hydroxide then from pillar with methanol.The vacuum concentration solute obtains title product.Productive rate: 100mg, 58%.HPLC-MS：M+1 ⁺＝345.5(UV/MS(％)＝99/99)。 ¹H?NMR(400MHz，CHCl ₃)：δ＝0.89(3H，t)，1.15-1.30(9H，m)，1.65(2H，broad?d)，1.81-1.89(4H，m)，2.30(3H，s)，2.36(2H，t)，2.86(2H，broad?d)，3.94(2H，dd)，4.51(2H，s)，6.76(1H，dd)，6.84(1H，d)，6.86(1H，d)。 ¹³C?NMR(CHCl ₃)：δ14.3，21.3，23.1，25.1，29.2，32.8(2C)，36.0，36.5，39.8，54.4(2C)，56.1，67.9，115.8，116.9，124.3，128.6，132.5，143.4，164.6。

6-acetyl group-4-[3-(4-butyl-piperidyl-1)-propyl group]-4H-benzo [1,4] oxazine-3-ketone (64-LHY-89-5)

[0427] according to synthetic 4-[3-(4-butyl-piperidyl-1)-propyl group]-method of 6-methyl-4H-benzo [1,4]-oxazines-3-ketone, [(96mg 0.5mmol) changes into title product to 1,4] oxazine-3-ketone with 6-acetyl group-4H-benzo.Productive rate: 120mg, 64%.HPLC-MS：M+1 ⁺＝373.5(UV/MS(％)＝99/100)。 ¹H?NMR(400MHz，CDCl ₃)：δ＝0.89(3H，t)，1.13-1.27(9H，m)，1.63(2H，broad?d)，1.81-1.88(4H，m)，2.37(2H，t)，2.55(3H，s)，2.84(2H，broad?d)，4.02(2H，dd)，4.65(2H，s)，6.99(1H，d)，7.58(1H，dd)，7.66(1H，d)。 ¹³C?NMR(CDCl ₃)：δ14.3，23.1，24.7，26.5，29.2，32.7(2C)，36.0，36.5，39.9，54.4(2C)，56.3，67.6，114.9，117.0，125.3，128.8，132.4，149.5，163.5，196.3。

4-[3-(4-butyl-piperidyl-1)-propyl group]-6-methyl-3,4-dihydro-2H-benzo [1,4] oxazine (64-LHY-91-6)

[0428] with the THF solution of borine (1M, 0.5mL 0.5mmol) are added to 4-[3-(4-butyl-piperidyl-1)-propyl group]-[(50mg is in THF 0.15mmol) (6mL) solution for 1,4] oxazine-3-ketone for 6-methyl-4H-benzo.Reactant mixture stirs down 16h at 40 ℃, at room temperature dropwise add then the HCl aqueous solution (4M, 10mL).Reactant mixture stirs 16h, vacuum concentration then.Add K ₂CO ₃(0.5g) water-soluble (5mL) solution of being become, product is with dichloromethane (2 * 10mL) extractions.Dry (Na ₂SO ₄) organic layer, vacuum concentration.In that Isco CombiFlash Sq 16 * (the 4g silica column is with containing the heptane+1%Et of 0-20% ethyl acetate ₃The N eluting) goes up purified product.Productive rate: 29.2mg, 56%.HPLC-MS：M+1 ⁺＝373.5(UV/MS(％)＝95/90)。 ¹H NMR (400MHz, CDCl ₃): δ=0.90 (3H, t), 1.18-1.35 (9H, m), 1.68 (2H, broad d), 1.78 (2H, quinoline), 1.89 (2H, broad t), 2.24 (3H, s), 2.35 (2H, t), 2.89 (2H, broad d), 3.27 (2H, t), 3.31 (2H, t), 4.19 (2H, t), 6.39 (1H, broad d), (6.52 1H, broad s), 6.66 (1H, d). ¹³C?NMR(CHCl ₃)：δ14.3，21.4，23.1，24.2，29.3，32.8(2C)，36.1，36.6，47.4，49.3，54.5(2C)，56.5，64.7，113.0，116.2，117.7，131.1，135.3，142.0。

4-[3-(4-butyl-piperidyl-1)-propyl group]-6-ethyl-3.4-dihydro-2H-benzo [1,4] oxazine (64-LHY-91-5)

[0429] according to synthetic 4-[3-(4-butyl-piperidyl-1)-propyl group]-6-methyl-3; 4-dihydro-2H-benzo [method of 1,4] oxazine is with 6-acetyl group-4-[3-(4-butyl-piperidyl-1)-propyl group]-4H-benzo [1; (60mg 0.161mmol) changes into title product to 4] oxazine-3-ketone.Productive rate: 22mg, 40%.HPLC-MS：M+1 ⁺＝373.5(UV/MS(％)＝98/97)。 ¹H NMR (400MHz, CDCl ₃): δ=0.89 (3H, t), 1.18-1.35 (12H, m), 1.68 (2H, broad d), 1.75 (2H, quinoline), 1.89 (2H, broad t), 2.35 (2H, t), 2.53 (2H, qv), (2.89 2H, broad d), and 3.26-3.33 (4H, m), 4.20 (2H, t), 6.43 (1H, dd), 6.53 (1H, d), 6.69 (1H, d). ¹³C?NMR(CHCl ₃)：δ14.3，16.2，23.1，24.2，28.9，29.3，32.8(2C)，36.1，36.6，47.4，49.4，54.5(2C)，56.5，64.7，112.0，116.2，116.5，135.3，137.7，142.2。

4-(3-chloropropyl)-4H-benzo [1,4] thiazine-3-ketone (81MF07)

[0430] under nitrogen with 2H-1,4-benzothiazine-3 (4H)-ketone (1.0g, 6.05mmol) and Cs ₂CO ₃(2.96g 9.08mmol) is dissolved in the dry acetonitrile (20mL), and at room temperature stirs 30min.By injection add the 3-chloro-propyl iodide be dissolved in the acetonitrile (4mL) (1.37g, 6.66mmol).Reactant mixture at room temperature stirred 18 hours, vacuum concentration.Add entry (150mL), (3 * 150mL) extract reactant mixture with ethyl acetate.Merge organic facies, dry (MgSO ₄), vacuum concentration.Obtain crude product 1.45g.Crude product is through CC[eluent: heptane: EtOAc (4: 1)], obtain pale yellow buttery pure title compound.Productive rate: 1.37g, 90.2%.R _f=0.24[heptane: EtOAc (4: 1)], ¹HNMR (CHCl ₃): δ 2.14 (m, 2H), 3.38 (s, 2H), 3.36 (t, 2H), 4.17 (t, 2H), 7.03 (t, 1H), 7.18 (d, 1H), 7.26 (t, 1H), 7.37 (d, 1H). ¹³C?NMR(CDCl ₃)：δ30.61，31.81，42.48，42.66，117.87，123.78，124.29，127.52，127.52，128.78，139.40，165.51。

4-[3-(4-butyl-piperidyl-1)-propyl group]-4H-benzo [1,4] thiazine-3-ketone (81MF09)

[0431] in acetonitrile (10mL), stir under the room temperature NaI (1.24g, 8.27mmol), K ₂CO ₃(1.14g, 8.27mmol) and the 4-butyl piperidine (0.62g, 4.34mmol).By injection add 4-(3-chloropropyl)-4H-benzo [1, the 4] thiazine-3-ketone be dissolved in the acetonitrile (15mL) (1.0g, 4.14mmol).In nitrogen, will be reflected at 60 ℃ and stir 13 hours down, then 80 ℃ of following restir 25 hours, vacuum concentration.Add entry (1 50mL), (3 * 150mL) extract reactant mixture with ethyl acetate.Merge organic facies, dry (Na ₂SO ₄), vacuum concentration.Obtain crude product 1.63g.Crude product process CC[eluent: EtOAc: MeOH (100: 1-5%)], obtain title compound.Productive rate: 1.06g, 74.2%HPLC-MS:[M+H] ⁺347 (UV/MS (%)=100/99. ¹HNMR(CHCl ₃)：δ0.88(t，3H)，1.23(m，9H)，1.64(d，2H)，1.85(m，4H)，2.34(t，2H)，2.83(d，2H)，3.36(s，1H)，4.03(t，2H)，6.99(m，1H)，7.22(d，2H)，7.34(d，1H)， ¹³C?NMR(CHCl ₃)：δ14.21，23.03，25.23，29.15，31.80，32.63，35.90，36.44，43.28，54.26，55.91，118.18，123.45，124.17，127.27，128.56，139.63，165.19。

[0432] to the 4-[3-that is dissolved in the 30ml ether (4-butyl-piperidyl-1)-propyl group]-4H-benzo [1,4] thiazine-3-ketone (1.06g, add in mmol) oxalic acid be dissolved in ether (5mL) (0.28g, 3.1mmol).Filter the crystal that forms, (5 * 10mL) wash, and obtain the oxalates of 1.21g after the drying with ether.HPLC-MS[M+H] ⁺347(UV/MS(％)＝100/99。

4-(3-chloropropyl)-4H-benzo [1,4] oxazine-3-ketone (81MF08)

[0433] under nitrogen with 2H-1,4-benzoxazinyl-3 (4H)-ketone (1.0g, 6.70mmol) and Cs ₂CO ₃(3.28g 10.1mmol) is dissolved in the dry acetonitrile (20mL), and at room temperature stirs 30min.By injection add the 3-chloro-propyl iodide be dissolved in the acetonitrile (4mL) (1.58g, 7.38mmol).Reactant mixture at room temperature stirred 18 hours, vacuum concentration.Add entry (150mL), (3 * 150mL) extract reactant mixture with ethyl acetate.Merge organic facies, dry (MgSO ₄), vacuum concentration obtains crude product 1.65g.Crude product is through CC[eluent: heptane: EtOAc (4: 1)], obtain the colorless oil title compound.Productive rate: 1.36g, 89.2%.R _f=0.24[heptane: EtOAc (4: 1)], ¹HNMR (CHCl ₃): δ 2.16 (m, 2H), 3.62 (t, 2H), 4.10 (t, 2H), 4.59 (s, 2H), 7.00 (m, 2H), 7.05 (m, 2H), ¹³C NMR (CHCl ₃): δ 30.16,39.04, and 42.45,67.72,114.80,117.38,123.07,124.14,128.49,145.47,164.58.

4-[3-(4-butyl-piperidyl-1)-propyl group]-4H-benzo [1,4] oxazine-3-ketone (81MF10)

[0434] in acetonitrile (10mL), stir under the room temperature NaI (1.33g, 8.87mmol), K ₂CO ₃(1.23g, 8.90mmol) and the 4-butyl piperidine (0.66g, 4.71mmol).By injection add 4-(3-the chloropropyl)-4H-benzo be dissolved in the acetonitrile (15mL) [1,4] oxazine-3-ketone (and 1.0g, 4.43mmol).In nitrogen, will be reflected at 60 ℃ and stir 13 hours down, then 80 ℃ of following restir 5 hours, vacuum concentration.Add entry (150mL), (3 * 150mL) extract reactant mixture with ethyl acetate.Merge organic facies, dry (Na ₂SO ₄), vacuum concentration gets crude product 1.58g.Crude product process CC[eluent: EtOAc: MeOH (100: 1-5%)], obtain pure title compound.Productive rate: 0.82g, 56.0%HPLC-MS[M+H] ⁺331 (UV/MS (%)=100/99. ¹HNMR(CHCl ₃)：δ0.88(t，3H)，1.21(m，6H)，1.26(m，3H)，1.66(d，2H)，1.86(m，4H)，2.37(t，2H)，2.86，(d，2H)，3.97(t，2H)，4.58(s，2H)，6.99(m，3H)，7.11(d，1H)， ¹³C?NMR(CHCl ₃)：δ14.22，23.04，24.90，29.17，32.68，35.95，36.46，39.74，54.31，56.02，67.77，115.26，117.15，122.83，123.83，128.78，145.50，164.34。

[0435] to the 4-[3-that is dissolved in the 30ml ether (4-butyl-piperidyl-1)-propyl group]-the 4H-benzo [1,4] oxazine-3-ketone (0.82g, add in mmol) oxalic acid be dissolved in ether (5mL) (0.25g, 2.8mmol).Filter the crystal that forms, (5 * 10mL) wash, and obtain the oxalates of 0.75g after the drying with ether.HPLC-MS[M+H] ⁺331(UV/MS(％)＝100/99。

Embodiment 2

Pharmacological datum

[0436] use clone's M1-M5 receptor to carry out acceptor selection and amplification (R-SAT) analysis, this kind analysis is disclosed by following document basically: Brauner-Osborne H, Brann MR.Pharmacology of muscarinic acetylcholine receptor subtypes (m1-m5): highthroughput assays in mammalian cells.Eur J Pharmacol 1996 Jan 4; 295 (1): 93-102, and Spalding TA, Trotter C, Skjaerbaek N, Messier TL, CurrierEA, Burstein ES, Li D, Hacksell U, Brann MR.Discovery of an ectopicactivation site on the M (1) m uscarinic receptor.Mol Pharmacol.2002 Jun; 61 (6): 1297-302.

The chemical compound sequence number	M1 effect %pEC ₅₀	M2 effect %pEC ₅₀	M3 effect %pEC ₅₀	M4 effect %pEC ₅₀	M5 effect %pEC ₅₀
The chemical compound sequence number	M1 effect %pEC ₅₀	M2 effect %pEC ₅₀	M3 effect %pEC ₅₀	M4 effect %pEC ₅₀	M5 effect %pEC ₅₀	??55-LH-28-1(1549)	?87????7.5	?41????5.8	Unreacted	??66????6.2	Unreacted
??77-LH-1(1606)	Unreacted	Unreacted	Unreacted	Unreacted	Unreacted	??55-LH-28-1(1549)	?87????7.5	?41????5.8	Unreacted	??66????6.2	Unreacted
??77-LH-1(1606)	Unreacted	Unreacted	Unreacted	Unreacted	Unreacted	??55-LH-28-8(1598)	?45????6.7	?67????＜5.5	Unreacted	??64????＜5.5	Not test
??55-LH-12-2	?72????7.3	?35????6.2	Unreacted	??68????6.0	Unreacted	??55-LH-28-8(1598)	?45????6.7	?67????＜5.5	Unreacted	??64????＜5.5	Not test
??55-LH-12-2	?72????7.3	?35????6.2	Unreacted	??68????6.0	Unreacted	??55LH44-A	?54????6.5	Unreacted	Unreacted	??28????＜5.5	Not test
??55LH54	?57????6.4	Unreacted	Unreacted	Unreacted	Unreacted	??55LH44-A	?54????6.5	Unreacted	Unreacted	??28????＜5.5	Not test
??55LH54	?57????6.4	Unreacted	Unreacted	Unreacted	Unreacted	??73MF01	?90????7.7	?55????6.3	Unreacted	??65????6.8	??49????6.2
??73MF02	?90????7.6	?50????6.0	Unreacted	??75????6.6	??30????6.3	??73MF01	?90????7.7	?55????6.3	Unreacted	??65????6.8	??49????6.2
??73MF02	?90????7.6	?50????6.0	Unreacted	??75????6.6	??30????6.3	??77LH02-1917	?55????6.7	Unreacted	Unreacted	??37????＜5.5	Unreacted
??64LHY89-5	?45????5.6	Unreacted	Unreacted	Unreacted	Not test	??77LH02-1917	?55????6.7	Unreacted	Unreacted	??37????＜5.5	Unreacted
??64LHY89-5	?45????5.6	Unreacted	Unreacted	Unreacted	Not test	??64LHY89-6	?80????7.4	?35????6.2	Unreacted	??50????6.5	??48????6.2
??64LHY91-5	?69????6.8	Unreacted	Unreacted	??51????5.7	??38????6.2	??64LHY89-6	?80????7.4	?35????6.2	Unreacted	??50????6.5	??48????6.2
??64LHY91-5	?69????6.8	Unreacted	Unreacted	??51????5.7	??38????6.2	??64LHY91-6	?86????7.2	?31????6.9	Unreacted	??52????6.6	Unreacted
??77LH22-A	?76????7.1	Unreacted	Unreacted	Unreacted	??37????＜5.5	??64LHY91-6	?86????7.2	?31????6.9	Unreacted	??52????6.6	Unreacted
??77LH22-A	?76????7.1	Unreacted	Unreacted	Unreacted	??37????＜5.5	??82LHY19	?81????7.7	?39????6.3	Unreacted	??46????6.8	Not test
??77LH61-A	?79????7.5	?28????＜5.5	Unreacted	??33????5.8	??51????＜5.5	??82LHY19	?81????7.7	?39????6.3	Unreacted	??46????6.8	Not test
??77LH61-A	?79????7.5	?28????＜5.5	Unreacted	??33????5.8	??51????＜5.5	??81MF24	?96????7.8	?70????7.0	Unreacted	Not test	Not test
??81MF763	?92????7.5	?47????6.6	Unreacted	??57????6.4	??50????5.9	??81MF24	?96????7.8	?70????7.0	Unreacted	Not test	Not test
??81MF763	?92????7.5	?47????6.6	Unreacted	??57????6.4	??50????5.9	??85LM47A	?122???7.9	?74????6.0	Unreacted	??91????6.1	??35????＜5.5
??85LM96-86R	?106???7.6	?97????6.2	????30????5.9	??94????5.8	??90????5.6	??85LM47A	?122???7.9	?74????6.0	Unreacted	??91????6.1	??35????＜5.5
??85LM96-86R	?106???7.6	?97????6.2	????30????5.9	??94????5.8	??90????5.6	??85LM96-87R	?101???7.7	?116???5.9	????36????6.0	??140????6.1	??62????6.0
??107LH55	?103???8.9	?28????7.5	Unreacted	??54????7.3	Unreacted	??85LM96-87R	?101???7.7	?116???5.9	????36????6.0	??140????6.1	??62????6.0
??107LH55	?103???8.9	?28????7.5	Unreacted	??54????7.3	Unreacted	??108LM39-36	?106???8.8	?37????8.1	Unreacted	??71????7.7	Unreacted
??107LH74-3D	?97????8.0	Unreacted	Not test	Not test	Not test	??108LM39-36	?106???8.8	?37????8.1	Unreacted	??71????7.7	Unreacted
??107LH74-3D	?97????8.0	Unreacted	Not test	Not test	Not test	??112KK20-c5	?117???8.3	Unreacted	Unreacted	Not test	Not test
??107LH95-1	?103???7.6	Unreacted	Not test	Not test	Not test	??112KK20-c5	?117???8.3	Unreacted	Unreacted	Not test	Not test

Claims

1. chemical compound shown in the general formula I and salt thereof and isomer

M is 0,1 or 2;

C ₃-C ₄Be CH ₂-CH or CH=C, perhaps C ₄Be CH and C ₃Do not exist;

Y is selected from O, S and H ₂

2. chemical compound as claimed in claim 1, wherein R ¹Can be selected from the C that selectively replaces _1-6-alkyl, the C that selectively replaces _1-6-alkylidene and the O-C that selectively replaces _1-6-alkyl.

3. chemical compound as claimed in claim 1 is wherein selected R ², R ³, m, C ₃-C ₄Make

Be selected from

4. chemical compound as claimed in claim 1, wherein R ²And R ³Be hydrogen, or select C ₃-C ₄, m, R ², R ³Make R ²And R ³Form ring system together, thereby

Be selected from

5. chemical compound as claimed in claim 1, wherein R ²And R ³The C that be independently selected from hydrogen, selectively replaces _1-6Alkyl, the O-C that selectively replaces _1-6Alkyl, halogen and hydroxyl.

6. chemical compound as claimed in claim 1, wherein m is 1.

7. chemical compound as claimed in claim 1, wherein m is 0, C ₃There is not C ₄Be CH,

Thereby

Be

8. chemical compound as claimed in claim 1, wherein X is selected from-C (R ⁶) (R ⁷)-C (R ⁶) (R ⁷)-,-C (R ⁶)=C (R ⁷)-,-O-C (R ⁶) (R ⁷)-, C (R ⁶) (R ⁷)-O-,-S-C (R ⁶) (R ⁷)-,-C (R ⁶) (R ⁷)-S-,-N (R ^N)-C (R ⁶) (R ⁷)-,-C (R ⁶) (R ⁷)-N (R ^N)-.

9. chemical compound as claimed in claim 1, wherein Y is selected from O and H ₂

10. chemical compound as claimed in claim 1, wherein L ¹And L ²Be independently selected from-C (R ⁶)=C (R ⁷) ,-C (R ⁶)=N-reaches-N=C (R ⁷)-.

11. the chemical compound shown in the general formula I a as claimed in claim 1

R wherein ¹Be selected from the C that selectively replaces _1-6-alkyl, the C that selectively replaces _1-6-alkylidene, the C that selectively replaces _2-6-thiazolinyl, the C that selectively replaces _2-6-alkynyl, the O-C that selectively replaces _1-6-alkyl and the O-C that selectively replaces _2-6-thiazolinyl; And R ², R ³, R ⁴, X, Y, R ⁶And R ⁷By defined as claim 1.

12. chemical compound as claimed in claim 11, the wherein C that selectively replaces _1-6-alkyl is selected from unsubstituted C _1-6-alkyl and C _1-6-alkoxyalkyl, wherein Y is selected from O and H ₂, wherein X is selected from-C (R ⁶) (R ⁷)-C (R ⁶) (R ⁷)-,-C (R ⁶)=C (R ⁷)-,-O-C (R ⁶) (R ⁷)-, C (R ⁶) (R ⁷)-O-,-S-C (R ⁶) (R ⁷)-,-C (R ⁶) (R ⁷)-S-, wherein L ¹And L ²Be independently selected from-C (R ⁶)=C (R ⁷)-,-C (R ⁶)=N-and-N=C (R ⁷)-, reaches wherein R ⁴The C that be selected from hydrogen, halogen, hydroxyl, selectively replaces _1-6-alkyl and the O-C that selectively replaces _1-6Alkyl.

13 as claimed in claim 1, wherein the compound is selected from 1 - [3 - (4 - butyl - piperidin-1) - C Yl] -1,2,3,4 - tetrahydro - quinoline; 1 - [3 - (4 - butyl - piperidin-1) - propyl] -2 - methyl-1, 2,3, 4 - tetrahydro - Quinoline; 1 - [3 - (4 - butyl - piperidin-1) - propyl] -6 - methyl-1, 2,3,4 - tetrahydro - quinoline; 1 - [3 - ( 4 - D Yl - piperidin-1) - propyl]-8 - methyl-1, 2,3,4 - tetrahydro - quinoline; 1 - [3 - (4 - butyl - piperidin-1) - third Yl]-7 - fluoro-2 - methyl-1, 2,3,4 - tetrahydro - quinoline; 1 - [3 - (4 - butyl - piperidin-1) - propyl]-7 - trifluoroacetic Methyl-1, 2,3,4 - tetrahydro - quinoline; 1 - [3 - (4 - butyl - piperidin-1) - propyl] -3,4 - dihydro-1H-quinolin- -2 - One; 1 - [3 - (4 - butyl - piperidin-1) - propyl] -6 - methoxy-3 ,4 - dihydro-1H-quinolin-2 - one; 4 - [3 - (4 - butyl - piperidin-1) - propyl]-4H-benzo [1,4] thiazine-3 - one; 4 - [3 - (4 - butyl - piperazine pyridine -1) - propyl]-4H-benzo [1,4] oxazin-3 - one; 4 - [3 - (4 - butyl - piperidin-1) - propyl] -6 - methyl base -4H-benzo [1,4] oxazin-3 - one; 6 - acetyl-4 - [3 - (4 - butyl - piperidin-1) - propyl]-4H-benzo [1,4] oxazin-3 - one; 4 - [3 - (4 - butyl - piperidin-1) - propyl]-6 - methyl -3,4 - dihydro-2H-benzo [1,4] oxazine; 4 - [3 - (4 - butyl - piperidin-1) - propyl] -6 - ethyl-3 ,4 - dihydro-2H-benzo [1,4 ] evil Triazine; (R) -4 - [3 - (4 - piperidin-1-butyl) -2 - methyl-propyl]-4H-benzo [1,4] thiazine-3 - one; (R) -4 - [2 - methyl-3 - (4 - propoxy-piperidin-1 -) propyl]-4H-benzo [1,4] thiazine-3 - one; (R) -4 - [3 - (4 - butylene - piperidin-1)-2 - methyl - propyl]-4H-benzo [1,4] thiazine-3 - one; (R) -4 - [3 - (3 - butyl-8 - aza - bicyclo [3.2.1] octyl -8) -2 - methyl - propyl]-4H-benzo [1,4] thiophene -3 - one; (R) -4 - [2 - methyl-3 - (3 - pentyl-8 - aza - bicyclo [3.2.1] octyl -60 -) propyl]-4H-phenyl And [1,4] thiazine-3 - one; 4 - [3 - (4 - butyl-piperidin-1 -) propyl] -6,8 - dichloro-7 - methyl-4H-benzo [1,4] oxazin-3 - one; 4 - [3 - (4 - butyl - piperidin-1 -) propyl] -6,8 - dimethyl-4H-benzo [1,4 ] evil -3 - one (81MF2237F); 6 - tert-butyl-4 - [3 - (4 - butyl - piperidin-1 -) propyl]-4H-benzo [1,4] oxazin-3 - one; 4 - [3 - (4 - butyl-piperidin-1 -) propyl] -5 - methyl-4H-benzo [1,4] oxazin - 3 - Ketone; 4 - [3 - (4 - butyl-piperidin-1 -) propyl]-7 - methyl-4H-benzo [1,4] oxazin-3 - one; 4 - [3 - ( 4 - Butyl-piperidin-1 -) propyl]-6 - chloro-7 - nitro-4H-benzo [1,4] oxazin-3 - one; 4 - [3 - (4 - butyl piperazine Piperidine-1 -) propyl]-7 - chloro-4H-benzo [1,4] oxazin-3 - one; 4 - [3 - (4 - butyl-piperidin-1 -) C Yl] -6 - fluoro-4H-benzo [1,4] oxazin-3 - one; 4 - [3 - (4 - butyl-piperidin-1 -) propyl] -7,8 - difluoro- -4H-benzo [1,4] oxazin-3 - one; 4 - [3 - (4 - butyl-piperidin-1 -) propyl]-4H-pyrido [4,3-b] [1,4] thiazine-3 - one; 4 - [3 - (4 - propoxy-piperidin-1 -) propyl]-4H-benzo [1,4] thiazide 3 - one; 4 - [3 - (4 - propoxy-piperidin-1 -) propyl]-4H-benzo [1,4] oxazin-3 - one; 4 - [3 - (4 - D Piperidin-1 -) propyl]-7 - fluoro-4H-benzo [1,4] oxazin-3 - one; 4 - [3 - (4 - butylene piperidin-1 -) Propyl]-4H-benzo [1,4] thiazine-3 - one; 4 - [3 - (4 - butylene piperidin-1 -) propyl]-4H-benzo [1,4] Oxazin-3 - one; 4 - [3 - (3 - butylene -8 - aza - bicyclo [3.2.1] octyl -8) - propyl]-4H-benzo [1,4] Oxazin-3 - one; 4 - [3 - (4 - butyl-piperidin-1 -) propyl] -6 - methoxy-4H-benzo [1,4] oxazin-3 - one; 4 - [3 - (4 - butyl-piperidin-1 -) propyl] -6,8 - dichloro-7 - ethyl-4H-benzo [1,4] oxazin-3 - one; 4 - [3 - (4 - butyl-piperidin-1 -) propyl]-8 - fluoro-4H-benzo [1,4] oxazin-3 - one; 6 - bromo-4 - [3 - (4 - D Piperidin-1 -) propyl]-8 - fluoro-4H-benzo [1,4] oxazin-3 - one; 4 - [3 - (4 - butyl-piperidin-1 -) C Yl]-8 - isopropyl-4H-benzo [1,4] oxazin-3 - one; (R, S) -4 - [3 - (4 - piperidin-1-butyl) -2 - hydroxy Propyl] -6 - methyl-4H-benzo [1,4] oxazin-3 - one; (R, S) -4 - [3 - (4 - piperidin-1-butyl) -2 - hydroxy Propyl]-4H-benzo [1,4] oxazin-3 - one; (-) -4 - [3 - (4 - piperidin-1-butyl) -2 - hydroxy-propyl]-4H- Benzo [1,4] oxazin-3 - one; (R, S) -4 - [3 - (4 - piperidin-butyl) -2 - methoxy-propyl]-4H-benzo [1, 4] Oxazin-3 - one; (R, S) -4 - [2 - hydroxy - 3 - (3 - pentyl-bicyclo [3.2.1] octyl -8) - propyl]-4H-benzo [1,4] oxazin-3 - one; 4 - [2 - (4 - butyl-piperidin-1 - methyl) allyl]-4H-benzo [1,4] oxazin-3 - Ketone; (R, S) -4 - [3 - (4 - piperidinyl-1-butyl) -2 - fluoro-propyl]-4H-benzo [1,4] oxazin-3 - one; (S) -4 - [3 - (4 - butyl - piperidin-1)-2 - methyl - propyl]-4H-benzo [1,4] oxazin-3 - one; (R) -4 - [3 - (4 - piperidin-1-butyl) -2 - methyl-propyl]-4H-benzo [1,4] oxazin-3 - one; (R) -4 - [1 - Methyl-3 - (4 - piperidin-1-propoxy) - propyl]-4H-benzo [1,4] oxazin-3 - one; (R) -4 - [3 - (4 - inferior Piperidin-1-butyl) -2 - methyl-propyl]-4H-benzo [1,4] oxazin-3 - one; (R) -4 - [3 - (3 - butyl-8 - nitrogen Miscellaneous - bicyclo [3.2.1] octyl -8) -2 - methyl-propyl]-4H-benzo [1,4] oxazin-3 - one; (R) -4 - [2 - methyl- -3 - (3 - pentyl-8 - aza-bicyclo [3.2.1] octyl -60 -) propyl]-4H-benzo [1,4] oxazin-3 - one; (R) -6 - Fluoro-4 - [2 - methyl -3 - (4 - propoxy - piperidin-1) - propyl]-4H-benzo [1,4] oxazin-3 - one; (R) -4 - [3 - (4 - piperidin-1-butylene)-2 - methyl - propyl]-6 - fluoro-4H-benzo [1,4] oxazin-3 - one; (R) -4 - [3 - (4 - piperidin-1-butyl) -2 - methyl-propyl]-6 - fluoro-4H-benzo [1,4] oxazin-3 - one; (R) -4 - [3 - (3 - butyl-8 - aza-bicyclo [3.2.1] octyl -8) -2 - methyl-propyl]-6 - fluoro-4H-benzo [1, 4] Oxazin-3 - one; (R) -6 - fluoro-4 - [2 - methyl -3 - (3 - pentyl-8 - aza-bicyclo [3.2.1] octyl -8) - C Yl]-4H-benzo [1,4] oxazin-3 - one; (R) -4 - [3 - (4 - butyl-piperidin-1 -) 2 - methyl-propyl]-7 - fluorine -4H-benzo [1,4] oxazin-3 - one; (R) -7 - fluoro-4 - [2 - methyl -3 - (4 - propoxy-piperidin-1 -) C Yl]-4H-benzo [1,4] oxazin-3 - one; (R) -4 - [3 - (4 - butylene-1 piperidinyl) -2 - methyl-propyl]-7 - Fluoro-4H-benzo [1,4] oxazin-3 - one; (R) -4 - [3 - (3 - butyl-8 - aza-bicyclo [3.2.1] octyl -8) -2 - Methyl-propyl]-7 - fluoro-4H-benzo [1,4] oxazin-3 - one; (R) -7 - fluoro-4 - [2 - methyl -3 - (3 - pentyl - 8 - Nitrogen Azabicyclo [3.2.1] octyl -8) - propyl]-4H-benzo [1,4] oxazin-3 - one; (R) -4 - [3 - (4 - butyl-piperidine -1) - 2 - methyl - propyl] -6 - methoxy-4H-benzo [1,4] oxazin-3 - one; (R) -4 - [3 - (4 - butylene Piperidin-1) -2 - methyl-propyl] -6 - methoxy-4H-benzo [1,4] oxazin-3 - one; (R) -4 - [3 - (3 - D base -8 - Azabicyclo [3.2.1] octyl -8) -2 - methyl-propyl] -6 - methoxy-4H-benzo [1,4] oxazin-3 - one; (R) -6 - methoxy-4 - [2 - methyl -3 - (3 - pentyl-8 - aza - bicyclo [3.2.1] octyl -60 -) propyl]-4H-phenyl And [1,4] oxazin-3 - one; (R) -6 - methoxy-4 - [2 - methyl -3 - (4 - propoxy-piperidin-1 -) C Yl]-4H-benzo [1,4] oxazin-3 - one; (R) -6 - methyl-4 - [2 - methyl -3 - (4 - piperidin-1-propoxy) - Propyl]-4H-benzo [1,4] oxazin-3 - one; (R) -4 - [3 - (4 - butylene-1 piperidinyl) -2 - methyl-propyl Yl] -6 - methyl-4H-benzo [1,4] oxazin-3 - one; (R) -4 - [3 - (4 - piperidin-1-butyl) -2 - methyl-C Yl] -6 - methyl-4H-benzo [1,4] oxazin-3 - one; (R) -4 - [3 - (3 - butyl-8 - azabicyclo [3.2.1] oct- -8) -2 - methyl-propyl] -6 - methyl-4H-benzo [1,4] oxazin-3 - one; (R) -4 - [3 - (3 - pentyl-8 - aza Bicyclo [3.2.1] octyl -8) -2 - methyl-propyl] -6 - methyl-4H-benzo [1,4] oxazin-3 - one; 1 - [3 - (4 - C Piperidin-oxy-1 -) propyl] -3,4 - dihydro-1H-quinolin-2 - one; 1 - [3 - (4 - butyl-piperidin-1 -) C Yl] -6 - fluoro-3 ,4 - dihydro-1H-quinolin-2 - one; 6 - fluoro-1 - [3 - (4 - propoxy-piperidin-1 -) propyl] -3 4 - Dihydro-1H-quinolin-2 - one; (R, S) -1 - [3 - (4 - piperidin-1-butyl) -2 - methyl-propyl]-6 - fluoro-3 ,4 - two Hydrogen-1H-quinolin-2 - one; (R, S) -6 - fluoro-1 - [3 - (4 - piperidinyl-1-propoxy) -2 - methyl-propyl] -3,4 - two Hydrogen-1H-quinolin-2 - one; 1 - [3 - (4 - butyl-piperidin-1 -) propyl]-6 - chloro -3,4 - dihydro-1H-quinolin-2 - One; 1 - [3 - (4 - piperidin-1-butyl -) propyl] -6 - methyl-3 ,4 - dihydro-1H-quinolin-2 - one: 6 - methyl 1 - [3 - (4 - propoxy-piperidin-1 -) propyl] -3,4 - dihydro-1H-quinolin-2 - one; 1 - [3 - (4 - butyl piperazine pyridine -1 -) propyl]-7 - fluoro-3 ,4 - dihydro-1H-quinolin-2 - one; 1 - [3 - (4 - butyl-piperidin-1 -) propyl] - 5 - Methyl -3,4 - dihydro-1H-quinolin-2 - one; 1 - [3 - (4 - butyl-piperidin-1 -) propyl]-7 - methyl -3,4 - Hydrogen-1H-quinolin-2 - one; 1 - [3 - (4 - butyl-piperidin-1 -) propyl]-7 - fluoro-6 - methyl -3,4 - dihydro-1H- Quinolin-2 - one; 1 - [3 - (4 - butyl-piperidin-1 -) propyl] -6,7 - difluoro-3 ,4 - dihydro-1H-quinolin-2 - one ; 6,7 - difluoro-1 - [3 - (4 - propoxy-piperidin-1 -) propyl] -3,4 - dihydro-1H-quinolin-2 - one; (R, S) -1 - [3 - (4 - piperidin-1-butyl) -2 - methyl-propyl] -6,7 - fluoro -3,4 - dihydro-1H-quinolin-2 - ketone; (R, S) -6,7 - difluoro-1 - [3 - (4 - piperidin-1-propoxy) -2 - methyl-propyl] -3,4 - dihydro-1H-quinolin- -2 - One; 1 - [3 - (4 - piperidin-1-butyl -) propyl]-6 - fluoro-7 - methyl-3 ,4 - dihydro-1H-quinolin-2 - one; 6 - fluorine -7 - Methyl-1 - [3 - (4 - propoxy-piperidin-1 -) propyl] -3,4 - dihydro-1H-quinolin-2 - one; (R, S) -1 - [3 - (4 - piperidin-1-butyl) -2 - methyl-propyl]-6 - fluoro-7 - methyl-3 ,4 - dihydro-1H-quinoline morpholine -2 - One; (R, S) -6 - fluoro-7 - methyl-1 - [2 - methyl -3 - (4 - piperidin-1-propoxy) - propyl] -3,4 - dihydro- -1H-quinolin-2 - one; 1 - [3 - (4 - butyl - piperidin-1 -) propyl]-6 - fluoro-5 - methyl-3 ,4 - dihydro-1H- quinoline -2 - one; 6 - fluoro-5 - methyl-1 - [3 - (4 - propoxy-piperidin-1 -) propyl] -3,4 - dihydro-1H-quinolin-2 - Ketone; (R) -1 - [3 - (4 - piperidinyl-1-butyl) -2 - methyl-propyl] -3,4 - dihydro-1H-quinolin-2 - one; (R) -1 - [2 - methyl-3 - (4 - propoxy-piperidin-1 -) propyl] -3,4 - dihydro-1H-quinolin-2 - one; (R) -1 - [3 - (4 - butylene-1 piperidinyl) -2 - methyl-propyl] -3,4 - dihydro-1H-quinolin-2 - one; (R) -1 - [3 - (3 - butyl-8 - aza-bicyclo [3.2.1] octyl -8) -2 - methyl-propyl] -3,4 - dihydro-1H-quinolin- -2 - One; (R) -1 - [2 - methyl-3 - (3 - pentyl-8 - aza-bicyclo [3.2.1] octyl -60 -) propyl] -3,4 - hydrogen -1H-quinolin-2 - one; 1 - [3 - (4 - butyl-piperidin-1 -) propyl]-1H-quinolin-2 - one; 1 - [3 - (4 - propoxy Piperidin-1 -) propyl]-1H-quinolin-2 - one; 1 - [3 - (4 - butyl-piperidin-1 -) propyl]-6 - fluoro-1H- Quinolin-2 - one; 1 - [3 - (4 - butyl-piperidin-1 -) propyl] -6 - methyl-1H-quinolin-2 - one; 1 - [3 - (4 - Ding Piperidin-1 -) propyl]-7 - fluoro-1H-quinolin-2 - one; 1 - [3 - (4 - butyl-piperidin-1 -) propyl] -6 - methyl Oxy-1H-quinolin-2 - one; 1 - [3 - (4 - butyl-piperidin-1 -) propyl] -6 - chloro-1H-quinolin-2 - one; 1 - [3 - (4 - butyl-piperidin-1 -) propyl] -5 - methyl-1H-quinolin-2 - one; 1 - [3 - (4 - butyl - piperidinyl -1 -) Propyl]-7 - methyl-1H-quinolin-2 - one; (R) -1 - [3 - (4 - piperidin-1-butyl) -2 - methyl-C Yl]-1H-quinolin-2 - one; (R) -1 - [2 - methyl-3 - (4 - piperidin-1-propoxy) - propyl]-1H-quinolin-2 - One; 1 - [3 - (4 - piperidin-allyloxy-1 -) propyl]-1H-quinolin-2 - one; (R, S) -4 - [3 - (4 - butyl piperazine Piperidine-1) -2 - methyl-propyl] -6 - methyl-4H-benzo [1.4] oxazin-3 - one; (R, S) -4 - [2 - methyl-3 - ( 4 - Propoxy-piperidin-1 -) propyl] -6 - methyl-4H-benzo [1.4] oxazin-3 - one; (R, S) -4 - [3 - (4 - Aden Piperidine-1) -2 - methyl-propyl] -6 - methyl-4H-benzo [1.4] oxazin-3 - one; (R, S) -4 - [3 - (3 - D -8 - aza-bicyclo [3.2.1] octyl -8) -2 - methyl-propyl] -6 - methyl-4H-benzo [1.4] oxazin-3 - one; (R, S) -4 - [2 - methyl-3 - (3 - pentyl-8 - aza-bicyclo [3.2.1] octyl -60 -) propyl] -6 - methyl-4H-phenyl And [1.4] oxazin-3 - one; (R, S) -4 - [3 - (4 - piperidin-1-butyl) -2 - methyl-propyl]-6 - fluoro-4H-benzo [1.4] oxazin-3 - one; (R, S) -6 - fluoro-4 - [2 - methyl -3 - (4 - propoxy-piperidin-1 -) propyl]-4H-phenyl and [1.4] oxazin-3 - one; (R, S) -4 - [3 - (4 - butylene-1 piperidinyl) -2 - methyl-propyl]-6 - fluoro-4H-benzo [1.4] oxazin-3 - one; (R, S) -4 - [3 - (3 - butyl-8 - aza-bicyclo [3.2.1] octyl -8) -2 - methyl-propyl Yl] -6 - fluoro-4H-benzo [1.4] oxazin-3 - one; (R, S) -6 - fluoro-4 - [2 - methyl -3 - (3 - pentyl-8 - N mixed pairs Ring [3.2.1] octyl -60 -) propyl]-4H-benzo [1.4] oxazin-3 - one; (R, S) -4 - [3 - (4 - piperidinyl butyl -1) -2 - Methyl-propyl]-7 - fluoro-4H-benzo [1.4] oxazin-3 - one; (R, S) -7 - fluoro-4 - [2 - methyl -3 - (4 - C Piperidin-oxy-1 -) propyl]-4H-benzo [1.4] oxazin-3 - one; (R, S) -4 - [3 - (4 - piperidinyl butylene -1 -) -2 - Methyl-propyl]-7 - fluoro-4H-benzo [1.4] oxazin-3 - one; (R, S) -4 - [3 - (3 - butyl-8 - aza Bicyclo [3.2.1] octyl -8) -2 - methyl-propyl]-7 - fluoro-4H-benzo [1.4] oxazin-3 - one; (R, S) -7 - fluoro- -4 - [2 - methyl - 3 - (3 - pentyl-8 - aza-bicyclo [3.2.1] octyl -60 -) propyl]-4H-benzo [1.4] oxazine 3 - one; (R, S) -3 - [3 - (4 - piperidin-1-butyl) -2 - methyl-propyl]-3H-benzothiazol-2 - one; (R, S) -4 - [2 - methyl-3 - (4 - propoxy-piperidin-1 -) propyl]-3H-benzothiazol-2 - one; (R, S) -4 - [3 - (4 - butylene-1 piperidinyl) -2 - methyl-propyl]-3H-benzothiazol-2 - one; (R, S) -3 - [3 - (3 - butyl-8 - aza-bicyclo [3.2.1] octyl -8) -2 - methyl-propyl]-3H-benzothiazol-2 - Ketone; (R, S) -3 - [2 - methyl-3 - (3 - pentyl-8 - aza-bicyclo [3.2.1] octyl -60 -) propyl]-3H-benzothiazol Oxazol-2 - one; (R, S) -4 - [3 - (4 - piperidin-1-butyl) -2 - methyl-propyl]-4H-benzo [1,4] oxazin-3- - ketone; (R, S) -4 - [2 - methyl-3 - (4 - propoxy-piperidin-1 -) propyl]-4H-benzo [1,4] oxazin-3 - one; (R, S) -4 - [3 - (4 - butylene-1 piperidinyl) -2 - methyl-propyl]-4H-benzo [1,4] oxazin-3 - one; (R, S) -4 - [3 - (3 - butyl-8 - aza-bicyclo [3.2.1] octyl -8) -2 - methyl-propyl]-4H-benzo [1,4] evil -3 - one; (R, S) -4 - [2 - methyl-3 - (3 - pentyl-8 - aza-bicyclo [3.2.1] octyl -60 -) propyl]-4H- benzene And [1,4] oxazin-3 - one; (R, S) -4 - [3 - (4 - piperidin-1-butyl) -2 - methyl-propyl]-4H-benzo [1 , 4] Thiazine-3 - one; (R, S) -1 - [2 - methyl-3 - (4 - propoxy-piperidin-1 -) propyl]-4H-benzo [1,4] thiazole triazine 3 - one; (R, S) -4 - [3 - (4 - butylene-1 piperidinyl) -2 - methyl-propyl]-4H-benzo [1,4] thiazine-3 - ketone; (R, S) -4 - [3 - (3 - butyl-8 - aza-bicyclo [3.2.1] octyl -8) -2 - methyl-propyl]-4H-benzo [1,4] thiophene -3 - one; (R, S) -4 - [2 - methyl-3 - (3 - pentyl-8 - aza-bicyclo [3.2.1] octyl -60 -) propyl]-4H- benzene And [1,4] thiazine-3 - one; (R, S) -1 - [3 - (4 - piperidin-1-butyl) -2 - methyl-propyl] -3,4 - dihydro- -1H- Quinolin-2 - one; (R, S) -1 - [2 - methyl-3 - (4 - propoxy-piperidin-1 -) propyl] -3,4 - dihydro-1H-quinoline morpholine -2 - One; (R, S) -1 - [3 - (4 - butylene-piperidine-1-y1) -2 - methyl-propyl] -3,4 - dihydro-1H-quinolin-2 - ketone; (R, S) -1 - [3 - (3 - butyl-8 - aza-bicyclo [3.2.1] octyl -8) -2 - methyl-propyl] -3,4 - dihydro-1H- quinoline -2 - one; (R, S) -1 - [2 - methyl-3 - (3 - pentyl-8 - aza-bicyclo [3.2.1] octyl -60 -) propyl] -3, 4 - two Hydrogen-1H-quinolin-2 - one; (R, S) -4 - [3 - (4 - piperidinyl-1-butyl) -2 - methyl-propyl] -6 - methoxy-4H- Benzo [1,4] oxazin-3 - one; (R, S) -4 - [2 - methyl-3 - (4 - piperidin-1-propoxy)-6 - methoxy] - 4H- Benzo [1,4] oxazin-3 - one; (R, S) -4 - [3 - (4 - butylene-1 piperidinyl) -2 - methyl-propyl] -6 - methoxy- -4H-benzo [1,4] oxazin-3 - one; (R, S) -4 - [3 - (3 - butyl-8 - aza-bicyclo [3.2.1] octyl -8) - 2 - A Yl-propyl] -6 - methoxy-4H-benzo [1,4] oxazin-3 - one; (R, S) -1 - [2 - methyl-3 - (3 - pentyl-8 - Nitrogen Azabicyclo [3.2.1] octyl -60 -) propyl] -6 - methoxy-4H-benzo [1,4] oxazin-3 - one; (R, S) -4 - [3 - (4 - piperidin-1-butyl) -2 - methyl-propyl] -6,7 - difluoro-4H-benzo [1,4] oxazin - 3 - one; (R, S) -6,7 - difluoro-4 - [2 - methyl -3 - (3 - pentyl-8 - aza-bicyclo [3.2.1] octyl -60 -) propyl]-4H - Benzene And [1,4] oxazin-3 - one; (R, S) -4 - [3 - (3 - butoxy-8 - aza-bicyclo [3.2.1] octyl -8) -2 - methyl base Propyl]-6 - fluoro-4H-benzo [1,4] oxazin-3 - one; (R, S) -6 - fluoro-4 - {3 - [3 - (2 - methoxyethyl ) -8 - Azabicyclo [3.2.1] octyl -8 -] -2 - methyl-propyl}-4H-benzo [1,4] oxazin-3 - one; (R, S) -4 - [3 - (3 - butyl-azetidin) -2 - methyl-propyl]-6 - fluoro-4H-benzo [1,4] oxazin-3- - Ketone; (R, S) -6 - fluoro-4 - [2 - methyl -3 - (3 - propoxy-azetidin -) propyl]-4H-benzo [1,4] evil -3 - one; (R, S) -4 - [3 - (3 - butyl-azetidin) -2 - methoxy-propyl]-6 - fluoro-4H-benzo [1,4] oxazin-3 - one; 4 - [3 - (4 - butyl-3 - droperidol-1) -2 - methyl-propyl]-6 - fluoro-4H-benzo [ 1,4] Oxazin-3 - one. ...

14. a compositions, it contains

I) chemical compound of one or more general formula Is as claimed in claim 1, and

Ii) at least a pharmaceutically acceptable excipient or carrier.

15. a method for the treatment of mammalian diseases, wherein the activity of cholinoceptor is regulated relevantly with the useful reaction of physiology in the described mammiferous described disease, and described method comprises the compound administration with the general formula I as claimed in claim 1 of effective dose.

16. method as claimed in claim 15, wherein said cholinoceptor is a muscarinic receptor.

17. method as claimed in claim 15, wherein said cholinoceptor are muscarinic M ₁-receptor subtype.

18. method as claimed in claim 15, wherein said cholinoceptor are muscarinic M ₄-receptor subtype.

19. method as claimed in claim 15, useful reaction of wherein said physiology and muscarinic M ₁-receptor subtype is with respect to muscarinic M ₂-or M ₃The selectivity of-receptor subtype is regulated relevant.

20. method as claimed in claim 15, wherein said chemical compound is a muscarinic agonist.

21. a method that improves cholinergic receptor activity, described method comprise that the system that makes cholinoceptor or contain cholinoceptor contacts with the chemical compound at least a as claimed in claim 1 of effective dose.

22. a treatment or prevention or alleviate method with mammiferous not normal relevant symptom, described method comprises the compound administration at least a as claimed in claim 1 with effective dose, and is described not normal relevant with muscarinic receptor, as with M ₁The muscarinic receptor hypotype is relevant.

23. method as claimed in claim 22, wherein said not normal cognitive impairment, forgetful, confusion, memory loss, attention disappearance, the blindness, depression, pain, sleep disordered, psychosis and the intraocular pressure of being selected from increases.

24. method as claimed in claim 22, wherein said not normal be selected from neurodegenerative disease, Alzheimer disease, Parkinson's disease, schizophrenia, Huntington chorea, family ataxia, Ji Liedela tell auspicious syndrome, Down's syndrome, Niemann-Pick disease, dementia, clinical melancholia, with age cognitive decline, attention deficiency, sudden infant death syndrome and glaucoma relatively.

25. method as claimed in claim 15, wherein said disease or not normal be Mental Subnormality, the useful reaction of wherein said physiology is because to M ₁Agonism, M ₁And M ₄Agonism, M ₁Agonism and D ₂Antagonism or M ₁And M ₄Agonism and D ₂The adjusting of antagonism.

27. be used for the treatment of purposes in disease relevant or the not normal medicine in preparation with cholinoceptor or its part as chemical compound, its pharmaceutically acceptable salt, its stereoisomer of each described general formula I in the claim 1～14 or the pharmaceutical composition that contains any above-mentioned substance.

28. chemical compound as each described general formula I in the claim 1～14, its pharmaceutically acceptable salt, its stereoisomer or the pharmaceutical composition that contains any above-mentioned substance are used for the treatment of the purposes that is selected from following disease or the not normal medicine in preparation: Alzheimer disease, Parkinson's disease, schizophrenia, Huntington chorea, family ataxia, Ji Liedela tells auspicious syndrome, Down's syndrome, Niemann-Pick disease, dull-witted, clinical melancholia, with age cognitive decline relatively, cognitive impairment, forgetful, confusion, lose memory, note disappearance, the blindness, depressed, pain, sleep disordered, psychosis, sudden infant death syndrome, intraocular pressure increases and glaucoma.